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CN103957706A - Estrogen receptor ligands and methods of use thereof - Google Patents

Estrogen receptor ligands and methods of use thereof Download PDF

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Publication number
CN103957706A
CN103957706A CN201280051979.4A CN201280051979A CN103957706A CN 103957706 A CN103957706 A CN 103957706A CN 201280051979 A CN201280051979 A CN 201280051979A CN 103957706 A CN103957706 A CN 103957706A
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compound
another embodiment
prostate cancer
yuan
formula
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J·多尔顿
M·S·斯坦纳
C·C·科斯
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Oncternal Therapeutics Inc
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GTx Inc
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Priority claimed from US13/215,679 external-priority patent/US9427418B2/en
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Priority claimed from PCT/US2012/052141 external-priority patent/WO2013043304A1/en
Publication of CN103957706A publication Critical patent/CN103957706A/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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/16—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
    • 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
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • 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

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Steroid Compounds (AREA)

Abstract

The present invention relates to methods for reducing testosterone levels by reduction of luteinizing hormone (LH) or independent of LH levels in a male subject and methods of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting prostate cancer, advanced prostate (5) cancer, castration resistant prostate cancer (CRPC), metastatic castration resistant prostate cancer (mCRPC) and palliative treatment of prostate cancer, advanced prostate cancer, castration resistant prostate cancer (CRPC) and metastatic castration resistant prostate cancer (mCRPC), and methods of reducing high or increasing PSA levels and/or increasing SHBG levels in a subject suffering from prostate cancer, advanced prostate cancer, castration resistant prostate cancer (CRPC) and metastatic (10) castration resistant prostate cancer (mCRPC). The compounds of this invention suppress free or total testosterone levels despite castration levels secondary to ADT and reduce high or increasing PSA levels.

Description

Estrogen receptor ligands with and using method
Invention field
The present invention relates to be used for the treatment of, to suppress castration resistance prostate cancer (CRPC) and its symptom, reduce its incidence of disease, reduce its seriousness or suppress its progress or increase suffers from the male sex's of CRPC the method for survival rate, and relate to for reducing suffering from serum PSA (PSA) level in the male subject of castration resistance prostate cancer (CRPC) and the method for level of serum testosterone.
Background of invention
Oestrogenic hormone refers to for tissue and sclerotin important and for organizing one group of endogenous and the synthetic hormone maintaining with sclerotin maintaining.Oestrogenic hormone be the growth of genital system and maintain in internal secretion regulatory factor in related cell processes.Oestrogenic hormone hot flash and prevention effect in PMO after biology of reproduction, prevention menopause are fully established.Estradiol is main endogenous human estrin, and is all found in masculinity and femininity.
Oestrogenic hormone and antiestrogenic biological agent are by two kinds of different intracellular receptors, and estrogen receptor alpha (ER α) and erss (ER β) manifest.Endogenous estrogen is effective activator of two kinds of receptor subtypes normally.For example, estradiol serves as ER alfa agonists in many tissues, and described tissue comprises breast tissue, bone tissue, cardiovascular organization and central nervous system tissue.Selective estrogen receptor modulators differently works conventionally in different tissues.For example, SERM can be ER alpha-2 antagonists in breast, but in uterus, bone and cardiovascular system, can be part ER alfa agonists.Therefore the compound that serves as estrogen receptor ligands is applicable to treat multiple symptom and illness.
Prostate cancer is a kind of in the non-cutaneum carcinoma of the most often diagnosing out in the U.S. male sex, and is the second modal cause of disease of cancer mortality, expection in the U.S., in 2012, have 241,740 routine new cases and 28,472 examples dead.Pass through radiation or operation up to 30% are carried out the patients with prostate cancer of one-level treatment one-level treatment were developed to metastatic disease in 10 years.Within 1 year, nearly 50,000 patients will be developed metastatic disease, and described metastatic disease is called as metastatic CRPC (mCRPC).
Advanced prostate cancer patient carries out androgen-deprivation therapy (ADT), and described treatment is by luteinising hormone-releasing hormo (LHRH) activator, lhrh antagonist or passes through bilateral orchidectomy.
The one-level ADT that causes castration (the total testosterone levels <50ng/dL of serum) suffers from for initial therapy the patient that metastatic hormone is not treated prostate cancer.Symptom is along with ADT improves, but ADT can not cure these patients.Unfortunately, finally become castration resistance and these male sex of prostate gland cancer cell developed PD.The male sex who suffers from mCRPC has very bad prognosis, serious cancer related symptoms and the life expectancy that is less than 16 months.
In the male sex, androgen-deprivation therapy not only reduces testosterone levels, and reduces estrogen level, because oestrogenic hormone derives from the aromatization of testosterone, and the level of testosterone is subdued by ADT.Therefore, ADT is also reduced to oestrogenic hormone " castration " level.
The estrogen deficiency of androgen-deprivation therapy induction causes remarkable side effect, and described side effect comprises that hot flash, gynecomastia and mastalgia, bone-loss, bone mass and strength decreased, osteoporosis and mortality fracture, unfavorable lipid change and higher angiocardiopathy and miocardial infarction and depression and other emotional change.The many estrogen deficiency side effects that it is believed that ADT are alpha mediated by ER.
Leuprorelin acetate it is the synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GRH) (GnRH or LHRH).Leuprorelin acetate is the LHRH super-agonists of finally suppressing hypophysis LH secretion.Leuprorelin acetate serves as effective inhibitor of gonadotrophin secretion, thus the compacting that causes ovary and testicosteroid to generate.In human body, use leuprorelin acetate and cause the initial increase of the cyclical level of luteinizing hormone (LH) and follicle stimulating hormone (FSH), thereby cause the instantaneous increase of the level of gonadal steroids (be testosterone and protona, and be oestrone and estradiol) in the male sex in Pre-menopausal Women.Yet continuous administration leuprorelin acetate causes LH and FSH level to reduce.In the male sex, testosterone is reduced to castration level (lower than 50ng/dL).In Pre-menopausal Women, oestrogenic hormone is reduced to level after menopause.Testosterone is the known stimulus of prostatic cancerous cells.Therefore the effect of compacting testosterone secretion or inhibition testosterone is the necessary component of prostate cancer therapy.Leuprorelin acetate can be used for LH compacting, and LH compacting is serum testosterone is reduced and be reduced to castration level with treatment prostate cancer.
Before introducing LHRH activator, by the estrogen active increasing in hypophysis via oestrogenic hormone (being mainly diethylstilbestrol (DES)), realize castration testosterone levels.DES testosterone is suppressed horizontal to castration aspect with LHRH activator effective equally.With the patient of DES treatment, can not there is hot flash or bone-loss, but really have with using the ADT of LHRH activator, compare, more the gynecomastia of height ratio.Unfortunately, efficient, pure oestrogenic hormone (as DES and estradiol) is often relevant to the excessive risk of serious cardiovascular and thromboembolic complication, and described complication has limited their clinical practice.
Compound of the present invention is that on-steroidal selectivity swashs ER alfa agonists.In CRPC patient and metastatic CRPC (mCRPC) patient's treatment, the little molecule of these novelties by increasing serum or steroid hormone haptoglobin (SHBG) thus the level cyclical level that reduces free serum testosterone (stimulating the form of the testosterone of prostate growth and prostate cancer) further suppress the patient's who carries out ADT testosterone levels (that is, these patients' testosterone levels is in castration level).Because compound of the present invention is ER alfa agonists, so they also improve the side effect of estrogen deficiency, comprise following ability: maintain sclerotin, reduce the incidence of disease of hot flash and avoid conventionally relevant with antagonist to LHRH activator insulin resistance and unfavorable lipid to change.
Brief summary of the invention
In one embodiment, the invention provides a kind for the treatment of, compacting castration resistance prostate cancer (CRPC) and its symptom, reduce its incidence of disease, reduce its seriousness or suppress its progress or increase suffers from the male sex's of castration resistance prostate cancer the method for survival rate, it comprises the I compound of formula as described below or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose:
In one embodiment, the invention provides a kind of method that reduction suffers from the Serum PSA level in the male subject of castration resistance prostate cancer (CRPC), it comprises the I of the formula as described below compound of administering therapeutic effective dose.In another embodiment, compound is compound IV as described below.
In one embodiment, the invention provides a kind of method that reduction suffers from the level of serum testosterone in the male subject of castration resistance prostate cancer (CRPC), it comprises the I of the formula as described below compound of administering therapeutic effective dose.In another embodiment, compound is compound IV as described below.
In one embodiment, the present invention is directed to a kind of increase and suffer from the method for the serum-concentration of property in the experimenter of castration resistance prostate cancer (CRPC) or steroid hormone haptoglobin (SHBG), it comprises the I of the formula as described below compound of administering therapeutic effective dose.In another embodiment, compound is compound IV as described below.
In another embodiment, castration resistance prostate cancer (CRPC) is metastatic CRPC (mCRPC).In another embodiment, experimenter has prostate specific antigen (PSA) level high or that increase.In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, using of compound can not cause the side effect relevant to androgen-deprivation therapy (ADT).In another embodiment, the group that free the following forms is selected in side effect: hot flash, gynecomastia, body fat increase, bone-loss, BMD reduces and risk of bone fracture increases.In another embodiment, compound or isomer, pharmaceutically acceptable salt, medicinal product, hydrate or its any combination be with every day 125mg, every day 250mg or every day 500mg dosage use.
Accompanying drawing summary
At the conclusion part of this specification, particularly point out and be clearly claimedly considered as theme of the present invention.Yet, about tissue with method of operating together with target of the present invention, feature and advantage, by reference to accompanying drawing, read following detailed description and can understand best the present invention, in the accompanying drawings:
Fig. 1 is depicted in the Orally administered compound IV of 30mg/kg every day (the 0th day the first dosage) serum testosterone (solid line) level in complete male monkey and total androgen (dotted line) level afterwards.(referring to embodiment 8.)
Fig. 2 describes with the testosterone levels in the intact rats of compound IV (0.3,1,10,30mg/kg) treatment. irepresent the complete medium contrast of contrast, P<0.05.BLOQ value is quantizing to limit 0.08ng/mL place diagrammatically to represent.(referring to embodiment 9.)
Fig. 3 describes the inhibitory action of compound IV to 17 β-HSD5 enzymic activity.(referring to embodiment 12.)
Fig. 4 is depicted in the hematoblastic aggregation in vitro of situation servant that has DES, 17 beta estradiols (E2) and compound IV.To be rich in hematoblastic blood plasma (PRP) and hatch 30 seconds by medium, E2, DES or compound IV, the thrombin induction of Yong0.3 unit is assembled afterwards.The percentage that continues 5 minutes and gathering is expressed as to medium contrast is assembled in monitoring.(referring to embodiment 13.)
Fig. 5 describes the general synthetic schemes for the preparation of Compound I I to XII.(referring to embodiment 1.)
Fig. 6 describes the synthetic schemes for the preparation of compound IV.(referring to embodiment 2.)
Fig. 7 describes the synthetic schemes for the preparation of compound VI.(referring to embodiment 3.)
Fig. 8 describes the synthetic schemes for the preparation of Compound I X and X.(referring to embodiment 5.)
Testosterone levels in the intact rats that Fig. 9 is depicted in 24 hours, 72 hours and treats by the compound IV of 3mg/kg, 10mg/kg and 300mg/kg dosage afterwards for 168 hours.(referring to embodiment 9.)
Figure 10 describes by the intact rats of compound IV treatment of 0.3mg/kg, 1mg/kg, 3mg/kg, 10mg/kg and 30mg/kg dosage and LH level (Figure 10 A), FSH level (Figure 10 B), testosterone levels (Figure 10 C), weight of prostate level (Figure 10 D), seminal vesicle weight level (Figure 10 E) and the musculus levator ani weight (Figure 10 F) of the rat of male castration (ORX). irepresent the complete medium contrast of contrast, P<0.05. orepresent the contrast of contrast ORX medium, P<0.05.BLOQ value is quantizing to limit 0.08ng/mL place diagrammatically to represent.(referring to embodiment 9.)
Figure 11 describes by with various dose administered compound IV (Figure 11 A) and DES (Figure 11 B), the prostate size in intact rats and ORX rat.(referring to embodiment 15.)
Figure 12 describes the difference between DES and compound IV; DES and glucocorticoid receptor (GR) cross reaction, compound IV can (Figure 12 A).DES and androgen receptor (AR) cross reaction.DES slightly stimulates AR effect and slight suppresses (that is, it is partial agonist/antagonist), and compound IV can (Figure 12 B).DES eliminates estrogen-related receptor (ERR) trans-activation, and compound IV can (Figure 12 C).(referring to embodiment 15.)
Figure 13 describes compound IV effect to the decay of hot flash in morphine abstinence syndrome model of 5mg/kg, 10mg/kg, 15mg/kg and 30mg/kg dosage.Every group of 7 animals of N=.In 100%DMSO, use 17 β-E2 of 5mg/kg.(referring to embodiment 14.)
Figure 14 describes to continue 91 days by administered compound IV, and the dose dependent body weight (kg) of monkey reduces (under 100mg/kg approximately 20%).Do not observe the symptom of gynecomastia or super estrogenicity (hyperestrogenicity).(referring to embodiment 16.)
Figure 15 describes to compare with positive control (LHRH activator), and the dose dependent level of serum testosterone after every day Orally administered compound IV in monkey reduces (ng/mL).The testosterone levels of the monkey of the patient's of dotted line indication androgen deprivation testosterone levels and thick dashed line indication operation castration.(referring to embodiment 16.)
Figure 16 describes by baseline with at the 28th day administered compound IV, dose dependent prostate specific antigen (PSA) level (ng/mL) in monkey.With compound IV treatment, PSA level is considerably reduced.(referring to embodiment 16.)
Figure 17 describes, by the 6th week administered compound IV, to compare with positive control (LHRH activator), the dose dependent prostate volume that uses TRUS (TRUS) to measure in monkey.(referring to embodiment 16.)
Figure 18 describes by administered compound IV, the dose dependent organ weight of the percentage of monkey (prostate, seminal vesicle and testis) (Figure 18 A) in contrast at the 90th day.The weight of prostate (Figure 18 B) in monkey during ptomatopsia in 13 weeks after every day Orally administered compound IV.(referring to embodiment 16.)
Figure 19 describes by administered compound IV (100mg, 300mg, 600mg and 1000mg), the average total testosterone levels (nmol/L) of dose dependent in one section of period people between 1 to 11 day.(referring to embodiment 17.)
Figure 20 describes by administered compound IV (100mg, 300mg, 600mg and 1000mg), the average LH level of dose dependent (IU/L) in one section of period people between 1 to 10 day.(referring to embodiment 17.)
Figure 21 describes by administered compound IV (100mg, 300mg, 600mg and 1000mg), the average free testosterone level of dose dependent (pg/mL) in one section of period people between 1 to 10 day.(referring to embodiment 17.)
Figure 22 describes by administered compound IV (100mg, 300mg, 600mg and 1000mg), the dose dependent mean P SA level (μ g/L) in one section of period people between 1 to 10 day.(referring to embodiment 17.)
After Figure 23 is depicted in recovering for 14 days of administered compound IV, the dose dependent level of serum testosterone (ng/mL) in intact rats. irepresent the complete contrast of contrast, P<0.05.(referring to embodiment 10.)
Figure 24 describes to reduce percentage (research 3) with the blood-serum P SA in seven experimenters that suffer from castration resistance prostate cancer (CRPC) of 2000mg compound IV treatment.
Figure 25 describes the flow chart of descriptive study 6 programs (embodiment 27).
Figure 26 describes the research details of each compound IV clinical research in people experimenter: health, patients with prostate cancer and the castration resistance patients with prostate cancer (embodiment 25 and 26) of not treated.
Figure 27 describes from (Figure 27 A) in research 2 and research 5 the first patient of controlling with from SHBG that in the CRPC patient of the parallel ADT of carrying out of research 3, (Figure 27 B) induced by compound IV and the relation between SHBG and free testosterone percentage (T% dissociates).In research 2 and research 5 tests, after compound IV treatment in 28 days, baseline SHBG is induced about 150%-700% (Figure 27 A).The reduction strong correlation of SHBG induction and the T% that dissociates [free T (pg/mL)/total T (pg/mL) * 100].The recurrence of relation shows that approximately 400% induction of SHBG reduces relevant to approximately 75% of free T%.Cross over the compound IV of all dosage, just control patient in a large number and gather together in this scope.Importantly, even when only the compound IV treatment of 15 days is checked, also maintain this strong relation (Figure 27 B) in the CRPC patient of the parallel ADT of the carrying out from research 3.The symbol of opening represents baseline (BL) and closed compound IV treatment (embodiment 26) as described below for symbol.
Figure 28 is depicted in the 7th day (Figure 28 A); The 14th day (Figure 28 B); When the 21st day (Figure 28 C) and (Figure 28 D) compound IV treatment in the 28th day, from the variation of free testosterone percentage in the patients with prostate cancer of not treated of research 2 and 5, contrast the variation (embodiment 26) of PSA.
When being depicted in the 28th day, Figure 29 contrasts the variation of SHBG from the variation of PSA in the patients with prostate cancer of not treated of research 2 and 5.What the SHBG induction of broad range can realize PSA is greater than 50% minimizing (embodiment 25).
When being depicted in the 15th day (7 experimenters) and the 30th day (3 experimenters), Figure 30 contrasts the variation (embodiment 26) of PSA from the variation of free testosterone percentage in the castration resistance patients with prostate cancer of research 3.
Figure 31 describes to control from research 2 and 5 first the mol ratio (solid line) of time dependent SHBG in patients with prostate cancer and total testosterone.Dotted line represents time dependent free testosterone percentage (free T%) (embodiment 25).
Figure 32 describes the average valley of variation percentage control compounds IV of the SHBG that calculates as the research 1 based on the 28th day time and research 2 results, and is extrapolated to the more low dosage of 125mg, 250mg and 500mg.Even if this shows under compared with the compound IV of low dosage, SHBG still can be raised to is enough to suppress significantly free T% and PSA (embodiment 25).
Figure 33 describes the flow chart of descriptive study 3 programs (embodiment 26).
Should be appreciated that, for easy and clearly demonstrate for the purpose of, the key element showing in figure needn't be drawn in proportion.For example, for the sake of clarity, the size of some key elements can be amplified with respect to other key element.In addition, in the situation that thinking fit, reference number can repeat to be used to refer to corresponding or similar key element between accompanying drawing.
Detailed Description Of The Invention
In the following detailed description, having set forth many details fully understands of the present invention to provide.Yet, one skilled in the art will understand that and can in the situation that there is no these details, implement the present invention.In other cases, the method for knowing, program and component are not described in detail, in order to avoid make the present invention fuzzy.
In one embodiment, compound and/or the composition that comprises described compound can be for reducing the total serum testosterone levels in male subject as described herein.
In one embodiment, compound and/or the composition that comprises described compound can and reduce prostate specific antigen (PSA) for reducing the total serum testosterone levels in male subject as described herein.In one embodiment, the reduction of total serum testosterone levels is to castration level.In one embodiment, the reduction of total serum testosterone levels does not reach castration level.In one embodiment, the reduction of total serum testosterone levels is to lower than separately by the accessible level of ADT.
In one embodiment, compound and/or the composition that comprises described compound can be for reducing prostate specific antigen as described herein, and this is independent of its minimizing effect or shortage to testosterone levels.
In one embodiment, compound and/or the composition that comprises described compound can be for reducing the total serum testosterone levels in male subject as described herein, and wherein the reduction of total serum testosterone occurs by the reduction of serum luteinizing hormone (LH) level.
In one embodiment, compound and/or the composition that comprises described compound can be for reducing the total serum testosterone levels in male subject as described herein, and wherein the reduction of total serum testosterone is independent of the reduction of serum luteinizing hormone level.
In one embodiment, compound and/or the composition that comprises described compound can be for reducing the free serum testosterone percentage in male subject (free T%) as described herein.
In one embodiment, compound and/or the composition that comprises described compound can be used for the treatment of, suppress castration resistance prostate cancer (CRPC) and its symptom, reduce its incidence of disease, reduce its seriousness or suppress its progress or increase the survival rate of the male sex with castration resistance prostate cancer as described herein.In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, experimenter further accepts androgen-deprivation therapy.
In one embodiment, compound and/or the composition that comprises described compound can be with LHRH activator or antagonist combination for increasing progresson free survival rate or the total survival rates of suffering from the experimenter of prostate cancer as described herein.In another embodiment, prostate cancer is advanced prostate cancer.In another embodiment, prostate cancer is castration resistance prostate cancer (CRPC).In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, experimenter is operation castration.In another embodiment, experimenter is androgen deprivation.
In one embodiment, compound and/or the composition that comprises described compound can be for increasing the survival rates with the male sex of castration resistance prostate cancer (CRPC) as described herein.In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, experimenter further accepts androgen-deprivation therapy.
In one embodiment, the invention provides a kind of method that reduces the total serum testosterone levels in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is by formula I representation:
Wherein
Y is C (O) or CH 2;
R 1, R 2be hydrogen, halogen, hydroxyl, alkoxyl, cyano group, nitro, CF independently 3, N (R) 2, sulfonamide, SO 2r, alkyl, alkylhalide group, aryl, O-Alk-NR 5r 6or O-Alk-heterocycle, wherein heterocycle be 3 yuan to heterocycle 7 yuan of replacements or unsubstituted, be optionally aromatic;
R 3, R 4be hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxyl, cyano group, nitro, CF independently 3, NHCOR, N (R) 2, sulfonamide, SO 2r, alkyl, alkylhalide group, aryl or shielded hydroxyl;
R is alkyl, hydrogen, alkylhalide group, two alkylhalide groups, three alkylhalide groups, CH 2f, CHF 2, CF 3, CF 2cF 3, aryl, phenyl, halogen, thiazolinyl, CN, NO 2or OH;
R 5and R 6be the alkyl of hydrogen, phenyl, 1 to 6 carbon atom, 3 yuan to 7 yuan cycloalkyl, 3 yuan to 7 yuan heterocycles, 5 yuan to 7 yuan aryl independently; Or R 5and R 6form 3 yuan to 7 rings together with nitrogen-atoms;
J and k are 1 to 4 independently; And
Alk is that the straight chained alkyl of 1 to 7 carbon is, the cyclic alkyl of the branched alkyl of 1 to 7 carbon or 3 to 8 carbon.
In the other embodiment of method described herein, formula I compound is represented by formula IA:
R wherein 1, R 2, R 3, R 4, j and k define suc as formula I.In one embodiment, the invention provides a kind of method that reduces the total serum testosterone levels in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula II compound:
In one embodiment, the invention provides a kind of method that reduces the total serum testosterone levels in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula III compound:
In one embodiment, the invention provides a kind of method that reduces the total serum testosterone levels in male subject, it comprises compound or its isomer, medicinal product, pharmaceutically acceptable salt, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula IV compound:
In one embodiment, the invention provides a kind of method that reduces the total serum testosterone levels in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula V compound:
In one embodiment, the invention provides a kind of method that reduces the total serum testosterone levels in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula VI compound:
In one embodiment, the invention provides a kind of method that reduces the total serum testosterone levels in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula VII compound:
In one embodiment, the invention provides a kind of method that reduces the total serum testosterone levels in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula VIII compound:
In one embodiment, luteinizing hormone (LH) level in a kind of male subject of suffering from prostate cancer by reduction of the invention provides reduces the method for total serum testosterone levels, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula IX compound:
In one embodiment, the invention provides a kind of method that reduces the total serum testosterone levels in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula X compound:
In one embodiment, the invention provides a kind of method that reduces the total serum testosterone levels in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula XI compound:
In one embodiment, the invention provides a kind of method that reduces the total serum testosterone levels in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula XII compound:
In one embodiment, the invention provides a kind of method that reduces the free level of serum testosterone in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is by formula I representation:
Wherein
Y is C (O) or CH 2;
R 1, R 2be hydrogen, halogen, hydroxyl, alkoxyl, cyano group, nitro, CF independently 3, N (R) 2, sulfonamide, SO 2r, alkyl, alkylhalide group, aryl, O-Alk-NR 5r 6or O-Alk-heterocycle, wherein heterocycle be 3 yuan to heterocycle 7 yuan of replacements or unsubstituted, be optionally aromatic;
R 3, R 4be hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxyl, cyano group, nitro, CF independently 3, NHCOR, N (R) 2, sulfonamide, SO 2r, alkyl, alkylhalide group, aryl or shielded hydroxyl;
R is alkyl, hydrogen, alkylhalide group, two alkylhalide groups, three alkylhalide groups, CH 2f, CHF 2, CF 3, CF 2cF 3, aryl, phenyl, halogen, thiazolinyl, CN, NO 2or OH;
R 5and R 6be the alkyl of hydrogen, phenyl, 1 to 6 carbon atom, 3 yuan to 7 yuan cycloalkyl, 3 yuan to 7 yuan heterocycles, 5 yuan to 7 yuan aryl independently; Or R 5and R 6form 3 yuan to 7 rings together with nitrogen-atoms;
J and k are 1 to 4 independently; And
Alk is that the straight chained alkyl of 1 to 7 carbon is, the cyclic alkyl of the branched alkyl of 1 to 7 carbon or 3 to 8 carbon.
In the other embodiment of method described herein, formula I compound is represented by formula IA:
R wherein 1, R 2, R 3, R 4, j and k define suc as formula I.
In one embodiment, the invention provides a kind of method that reduces the free level of serum testosterone in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula II compound:
In one embodiment, the invention provides a kind of method that reduces the free level of serum testosterone in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula III compound:
In one embodiment, the invention provides a kind of method that reduces the free level of serum testosterone in male subject, it comprises compound or its isomer, medicinal product, pharmaceutically acceptable salt, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula IV compound:
In one embodiment, the invention provides a kind of method that reduces the free level of serum testosterone in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula V compound:
In one embodiment, the invention provides a kind of method that reduces the free level of serum testosterone in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula VI compound:
In one embodiment, the invention provides a kind of method that reduces the free level of serum testosterone in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula VII compound:
In one embodiment, the invention provides a kind of method that reduces the free level of serum testosterone in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula VIII compound:
In one embodiment, luteinizing hormone (LH) level in a kind of male subject of suffering from prostate cancer by reduction of the invention provides reduces the method for free level of serum testosterone, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula IX compound:
In one embodiment, the invention provides a kind of method that reduces the free level of serum testosterone in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula X compound:
In one embodiment, the invention provides a kind of method that reduces the free level of serum testosterone in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula XI compound:
In one embodiment, the invention provides a kind of method that reduces the free level of serum testosterone in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula XII compound:
In one embodiment, the invention provides a kind of method that reduces the free serum testosterone percentage (free T%) in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is by formula I representation:
Wherein
Y is C (O) or CH 2;
R 1, R 2be hydrogen, halogen, hydroxyl, alkoxyl, cyano group, nitro, CF independently 3, N (R) 2, sulfonamide, SO 2r, alkyl, alkylhalide group, aryl, O-Alk-NR 5r 6or O-Alk-heterocycle, wherein heterocycle be 3 yuan to heterocycle 7 yuan of replacements or unsubstituted, be optionally aromatic;
R 3, R 4be hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxyl, cyano group, nitro, CF independently 3, NHCOR, N (R) 2, sulfonamide, SO 2r, alkyl, alkylhalide group, aryl or shielded hydroxyl;
R is alkyl, hydrogen, alkylhalide group, two alkylhalide groups, three alkylhalide groups, CH 2f, CHF 2, CF 3, CF 2cF 3, aryl, phenyl, halogen, thiazolinyl, CN, NO 2or OH;
R 5and R 6be the alkyl group of hydrogen, phenyl, 1 to 6 carbon atom, 3 yuan to 7 yuan cycloalkyl, 3 yuan to 7 yuan heterocycles, 5 yuan to 7 yuan aryl independently; Or R 5and R 6form 3 yuan to 7 rings together with nitrogen-atoms;
J and k are 1 to 4 independently; And
Alk is that the straight chained alkyl of 1 to 7 carbon is, the cyclic alkyl of the branched alkyl of 1 to 7 carbon or 3 to 8 carbon.
In the other embodiment of method described herein, formula I compound is represented by formula IA:
R wherein 1, R 2, R 3, R 4, j and k define suc as formula I.
In one embodiment, the invention provides a kind of method that reduces the free serum testosterone percentage (free T%) in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula II compound:
In one embodiment, the invention provides a kind of method that reduces the free serum testosterone percentage (free T%) in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula III compound:
In one embodiment, the invention provides a kind of method that reduces the free serum testosterone percentage (free T%) in male subject, it comprises compound or its isomer, medicinal product, pharmaceutically acceptable salt, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula IV compound:
In one embodiment, the invention provides a kind of method that reduces the free serum testosterone percentage (free T%) in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula V compound:
In one embodiment, the invention provides a kind of method that reduces the free serum testosterone percentage (free T%) in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula VI compound:
In one embodiment, the invention provides a kind of method that reduces the free serum testosterone percentage (free T%) in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula VII compound:
In one embodiment, the invention provides a kind of method that reduces the free serum testosterone percentage (free T%) in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula VIII compound:
In one embodiment, luteinizing hormone (LH) level in a kind of male subject of suffering from prostate cancer by reduction of the invention provides reduces the method for free serum testosterone percentage (free T%), it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula IX compound:
In one embodiment, the invention provides a kind of method that reduces the free serum testosterone percentage (free T%) in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula X compound:
In one embodiment, the invention provides a kind of method that reduces the free serum testosterone percentage (free T%) in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula XI compound:
In one embodiment, the invention provides a kind of method that reduces the free serum testosterone percentage (free T%) in male subject, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula XII compound:
In one embodiment, the invention provides a kind for the treatment of, compacting castration resistance prostate cancer (CRPC) and symptom thereof, reduce its incidence of disease, reduce its seriousness or suppress its progress or increase the method for the male sex's who suffers from castration resistance prostate cancer survival rate, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is by formula I representation:
Wherein
Y is C (O) or CH 2;
R 1, R 2be hydrogen, halogen, hydroxyl, alkoxyl, cyano group, nitro, CF independently 3, N (R) 2, sulfonamide, SO 2r, alkyl, alkylhalide group, aryl, O-Alk-NR 5r 6or O-Alk-heterocycle, wherein heterocycle be 3 yuan to heterocycle 7 yuan of replacements or unsubstituted, be optionally aromatic;
R 3, R 4be hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxyl, cyano group, nitro, CF independently 3, NHCOR, N (R) 2, sulfonamide, SO 2r, alkyl, alkylhalide group, aryl or shielded hydroxyl;
R is alkyl, hydrogen, alkylhalide group, two alkylhalide groups, three alkylhalide groups, CH 2f, CHF 2, CF 3, CF 2cF 3, aryl, phenyl, halogen, thiazolinyl, CN, NO 2or OH;
R 5and R 6be the alkyl group of hydrogen, phenyl, 1 to 6 carbon atom, 3 yuan to 7 yuan cycloalkyl, 3 yuan to 7 yuan heterocycles, 5 yuan to 7 yuan aryl independently; Or R 5and R 6form 3 yuan to 7 rings together with nitrogen-atoms;
J and k are 1 to 4 independently; And
Alk is that the straight chained alkyl of 1 to 7 carbon is, the cyclic alkyl of the branched alkyl of 1 to 7 carbon or 3 to 8 carbon.
In the other embodiment of method described herein, formula I compound is represented by formula IA:
R wherein 1, R 2, R 3, R 4, j and k define suc as formula I.
In one embodiment, the invention provides a kind for the treatment of, compacting castration resistance prostate cancer (CRPC) and its symptom, reduce its incidence of disease, reduce its seriousness or suppress its progress or increase the method for the male sex's who suffers from castration resistance prostate cancer survival rate, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula II compound:
In one embodiment, the invention provides a kind for the treatment of, compacting castration resistance prostate cancer (CRPC) and its symptom, reduce its incidence of disease, reduce its seriousness or suppress its progress or increase the method for the male sex's who suffers from castration resistance prostate cancer survival rate, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula III compound:
In one embodiment, the invention provides a kind for the treatment of, compacting castration resistance prostate cancer (CRPC) and its symptom, reduce its incidence of disease, reduce its seriousness or suppress its progress or increase suffers from the male sex's of castration resistance prostate cancer the method for survival rate, it comprises compound or its isomer, medicinal product, pharmaceutically acceptable salt, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula IV compound:
In one embodiment, the invention provides a kind for the treatment of, compacting castration resistance prostate cancer (CRPC) and its symptom, reduce its incidence of disease, reduce its seriousness or suppress its progress or increase the method for the male sex's who suffers from castration resistance prostate cancer survival rate, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula V compound:
In one embodiment, the invention provides a kind for the treatment of, compacting castration resistance prostate cancer (CRPC) and its symptom, reduce its incidence of disease, reduce its seriousness or suppress its progress or increase the method for the male sex's who suffers from castration resistance prostate cancer survival rate, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula VI compound:
In one embodiment, the invention provides a kind for the treatment of, compacting castration resistance prostate cancer (CRPC) and its symptom, reduce its incidence of disease, reduce its seriousness or suppress its progress or increase the method for the male sex's who suffers from castration resistance prostate cancer survival rate, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula VII compound:
In one embodiment, the invention provides a kind for the treatment of, compacting castration resistance prostate cancer (CRPC) and its symptom, reduce its incidence of disease, reduce its seriousness or suppress its progress or increase the method for the survival rate of the male sex with castration resistance prostate cancer, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula VIII compound:
In one embodiment, the invention provides a kind for the treatment of, compacting castration resistance prostate cancer (CRPC) and its symptom, reduce its incidence of disease, reduce its seriousness or suppress its progress or increase the method for the male sex's who suffers from castration resistance prostate cancer survival rate, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula IX compound:
In one embodiment, the invention provides a kind for the treatment of, compacting castration resistance prostate cancer (CRPC) and its symptom, reduce its incidence of disease, reduce its seriousness or suppress its progress or increase the method for the male sex's who suffers from castration resistance prostate cancer survival rate, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula X compound:
In one embodiment, the invention provides a kind for the treatment of, compacting castration resistance prostate cancer (CRPC) and its symptom, reduce its incidence of disease, reduce its seriousness or suppress its progress or increase the method for the male sex's who suffers from castration resistance prostate cancer survival rate, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula XI compound:
In one embodiment, the invention provides a kind for the treatment of, compacting castration resistance prostate cancer (CRPC) and its symptom, reduce its incidence of disease, reduce its seriousness or suppress its progress or increase the method for the male sex's who suffers from castration resistance prostate cancer survival rate, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula XII compound:
In one embodiment, the invention provides a kind of reduction and suffer from the method for serum PSA (PSA) level in the male subject of castration resistance prostate cancer (CRPC), it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is by formula I representation:
Wherein
Y is C (O) or CH 2;
R 1, R 2be hydrogen, halogen, hydroxyl, alkoxyl, cyano group, nitro, CF independently 3, N (R) 2, sulfonamide, SO 2r, alkyl, alkylhalide group, aryl, O-Alk-NR 5r 6or O-Alk-heterocycle, wherein heterocycle be 3 yuan to heterocycle 7 yuan of replacements or unsubstituted, be optionally aromatic;
R 3, R 4be hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxyl, cyano group, nitro, CF independently 3, NHCOR, N (R) 2, sulfonamide, SO 2r, alkyl, alkylhalide group, aryl or shielded hydroxyl;
R is alkyl, hydrogen, alkylhalide group, two alkylhalide groups, three alkylhalide groups, CH 2f, CHF 2, CF 3, CF 2cF 3, aryl, phenyl, halogen, thiazolinyl, CN, NO 2or OH;
R 5and R 6be the alkyl group of hydrogen, phenyl, 1 to 6 carbon atom, 3 yuan to 7 yuan cycloalkyl, 3 yuan to 7 yuan heterocycles, 5 yuan to 7 yuan aryl independently; Or R 5and R 6form 3 yuan to 7 rings with nitrogen-atoms;
J and k are 1 to 4 independently; And
Alk is that the straight chained alkyl of 1 to 7 carbon is, the cyclic alkyl of the branched alkyl of 1 to 7 carbon or 3 to 8 carbon.
In the other embodiment of method described herein, formula I compound is represented by formula IA:
R wherein 1, R 2, R 3, R 4, j and k define suc as formula I.
In one embodiment, the invention provides a kind of reduction and suffer from the method for serum PSA (PSA) level in the male subject of castration resistance prostate cancer (CRPC), it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula II compound:
In one embodiment, the invention provides a kind of reduction and suffer from the method for serum PSA (PSA) level in the male subject of castration resistance prostate cancer (CRPC), it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula III compound:
In one embodiment, the invention provides a kind of reduction and suffer from the method for serum PSA (PSA) level in the male subject of castration resistance prostate cancer (CRPC), it comprises compound or its isomer, medicinal product, pharmaceutically acceptable salt, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula IV compound:
In one embodiment, the invention provides a kind of reduction and suffer from the method for serum PSA (PSA) level in the male subject of castration resistance prostate cancer (CRPC), it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula V compound:
In one embodiment, the invention provides a kind of reduction and suffer from the method for serum PSA (PSA) level in the male subject of castration resistance prostate cancer (CRPC), it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula VI compound:
In one embodiment, the invention provides a kind of reduction and suffer from the method for serum PSA (PSA) level in the male subject of castration resistance prostate cancer (CRPC), it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula VII compound:
In one embodiment, the invention provides a kind of reduction and suffer from the method for serum PSA (PSA) level in the male subject of castration resistance prostate cancer (CRPC), it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula VIII compound:
In one embodiment, the invention provides a kind of reduction and suffer from the method for serum PSA (PSA) level in the male subject of castration resistance prostate cancer (CRPC), it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula IX compound:
In one embodiment, the invention provides a kind of reduction and suffer from the method for serum PSA (PSA) level in the male subject of castration resistance prostate cancer (CRPC), it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula X compound:
In one embodiment, the invention provides a kind of reduction and suffer from the method for serum PSA (PSA) level in the male subject of castration resistance prostate cancer (CRPC), it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula XI compound:
In one embodiment, the invention provides a kind of reduction and suffer from the method for serum PSA (PSA) level in the male subject of castration resistance prostate cancer (CRPC), it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula XII compound:
In one embodiment, the invention provides and a kind ofly make castration (, testosterone levels is lower than 50ng/dL) CRPC patient in free testosterone percentage (free T%) be reduced to the independent method by the unreachable level of ADT, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is by formula I representation:
Wherein
Y is C (O) or CH 2;
R 1, R 2be hydrogen, halogen, hydroxyl, alkoxyl, cyano group, nitro, CF independently 3, N (R) 2, sulfonamide, SO 2r, alkyl, alkylhalide group, aryl, O-Alk-NR 5r 6or O-Alk-heterocycle, wherein heterocycle be 3 yuan to heterocycle 7 yuan of replacements or unsubstituted, be optionally aromatic;
R 3, R 4be hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxyl, cyano group, nitro, CF independently 3, NHCOR, N (R) 2, sulfonamide, SO 2r, alkyl, alkylhalide group, aryl or shielded hydroxyl;
R is alkyl, hydrogen, alkylhalide group, two alkylhalide groups, three alkylhalide groups, CH 2f, CHF 2, CF 3, CF 2cF 3, aryl, phenyl, halogen, thiazolinyl, CN, NO 2or OH;
R 5and R 6be the alkyl group of hydrogen, phenyl, 1 to 6 carbon atom, 3 yuan to 7 yuan cycloalkyl, 3 yuan to 7 yuan heterocycles, 5 yuan to 7 yuan aryl independently; Or R 5and R 6form 3 yuan to 7 rings together with nitrogen-atoms;
J and k are 1 to 4 independently; And
Alk is that the straight chained alkyl of 1 to 7 carbon is, the cyclic alkyl of the branched alkyl of 1 to 7 carbon or 3 to 8 carbon.
In the other embodiment of method described herein, formula I compound is represented by formula IA:
R wherein 1, R 2, R 3, R 4, j and k define suc as formula I.
In one embodiment, the invention provides and a kind ofly make castration (, testosterone levels is lower than 50ng/dL) CRPC patient in free testosterone percentage (free T%) be reduced to the independent method by the unreachable level of ADT, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula II compound:
In one embodiment, the invention provides and a kind ofly make castration (, testosterone levels is lower than 50ng/dL) CRPC patient in free testosterone percentage (free T%) be reduced to the independent method by the unreachable level of ADT, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula III compound:
In one embodiment, the invention provides and a kind ofly make castration (, testosterone levels is lower than 50ng/dL) CRPC patient in free testosterone percentage (free T%) be reduced to the independent method by the unreachable level of ADT, it comprises compound or its isomer, medicinal product, pharmaceutically acceptable salt, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula IV compound:
In one embodiment, the invention provides and a kind ofly make castration (, testosterone levels is lower than 50ng/dL) CRPC patient in free testosterone percentage (free T%) be reduced to the independent method by the unreachable level of ADT, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula V compound:
In one embodiment, the invention provides and a kind ofly make castration (, testosterone levels is lower than 50ng/dL) CRPC patient in free testosterone percentage (free T%) be reduced to the independent method by the unreachable level of ADT, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula VI compound:
In one embodiment, the invention provides and a kind ofly make castration (, testosterone levels is lower than 50ng/dL) CRPC patient in free testosterone percentage (free T%) be reduced to the independent method by the unreachable level of ADT, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula VII compound:
In one embodiment, the invention provides and a kind ofly make castration (, testosterone levels is lower than 50ng/dL) CRPC patient in free testosterone percentage (free T%) be reduced to the independent method by the unreachable level of ADT, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula VIII compound:
In one embodiment, the invention provides and a kind ofly make castration (, testosterone levels is lower than 50ng/dL) CRPC patient in free testosterone percentage (free T%) be reduced to the independent method by the unreachable level of ADT, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula IX compound:
In one embodiment, the invention provides and a kind ofly make castration (, testosterone levels is lower than 50ng/dL) CRPC patient in free testosterone percentage (free T%) be reduced to the independent method by the unreachable level of ADT, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula X compound:
In one embodiment, the invention provides and a kind ofly make castration (, testosterone levels is lower than 50ng/dL) CRPC patient in free testosterone percentage (free T%) be reduced to the independent method by the unreachable level of ADT, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula XI compound:
In one embodiment, the invention provides and a kind ofly make castration (, testosterone levels is lower than 50ng/dL) CRPC patient in free testosterone percentage (free T%) be reduced to the independent method by the unreachable level of ADT, it comprises compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and described compound is represented by formula XII compound:
In one embodiment, the invention provides a kind for the treatment of, compacting castration resistance prostate cancer (CRPC) and its symptom, reduce its incidence of disease, reduce its seriousness or suppress its progress or increase suffers from the male sex's of castration resistance prostate cancer the method for survival rate, it comprises formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose.In another embodiment, castration is operation castration.In another embodiment, castration is androgen deprivation.In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, described method is further treated, is suppressed new bone transfer, reduces its incidence of disease, reduces its seriousness or suppress new bone and shift.In another embodiment, described method is further treated, is suppressed soft tissue transfer (metatheses) (internal organ and lymph node) new or that worsen, reduces its incidence of disease, reduces its seriousness or suppress soft tissue new or that worsen and shift.In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts LHRH activator or antagonist.In another embodiment, LHRH activator is leuprorelin acetate.In another embodiment, experimenter has experienced orchiectomy.In another embodiment, experimenter has prostate specific antigen (PSA) level high or that increase.In another embodiment, using of compound can not cause the side effect relevant to androgen-deprivation therapy (ADT).In another embodiment, described method is further treated, is suppressed advanced prostate cancer, reduces its incidence of disease, reduces its seriousness or suppresses advanced prostate cancer.In another embodiment, described method further provides the palliative treatment of advanced prostate cancer.In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, a kind of method that the invention provides treatment, compacting castration resistance prostate cancer (CRPC) and its symptom, reduces its incidence of disease, reduces its seriousness or suppress its progress or increase the male sex's who suffers from castration resistance prostate cancer survival rate, it comprises estradiol, ethinyl estradiol, steroids estrogen agonist, on-steroidal estrogen agonist or its combination of administering therapeutic effective dose.
In one embodiment, the invention provides a kind of reduction and suffer from the method for the total serum testosterone levels in the male subject of castration resistance prostate cancer (CRPC), it comprises formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose.In another embodiment, castration is operation castration.In another embodiment, castration is androgen deprivation.In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, described method is further treated, is suppressed new bone transfer, reduces its incidence of disease, reduces its seriousness or suppress new bone and shift.In another embodiment, described method is further treated, is suppressed soft tissue transfer (internal organ and lymph node) new or that worsen, reduces its incidence of disease, reduces its seriousness or suppress soft tissue new or that worsen and shift.In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts LHRH activator or antagonist.In another embodiment, LHRH activator is leuprorelin acetate.In another embodiment, experimenter has experienced orchiectomy.In another embodiment, experimenter has prostate specific antigen (PSA) level high or that increase.In another embodiment, using of compound can not cause the side effect relevant to androgen-deprivation therapy (ADT).In another embodiment, described method is further treated, is suppressed advanced prostate cancer, reduces its incidence of disease, reduces its seriousness or suppresses advanced prostate cancer.In another embodiment, described method further provides the palliative treatment of advanced prostate cancer.In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.In another embodiment, total serum testosterone is reduced to lower than about 100ng/dL.In another embodiment, total serum testosterone is reduced to lower than about 50ng/dL.In another embodiment, total serum testosterone concentration is reduced to lower than about 25ng/dL.In another embodiment, total serum testosterone concentration is reduced to lower than about 10ng/dL.In another embodiment, total serum testosterone concentration is reduced to lower than about 5ng/dL.In another embodiment, total serum testosterone concentration is reduced to lower than about 1ng/dL.
In one embodiment, the invention provides a kind of reduction and suffer from the method for the total serum testosterone levels in the male subject of castration resistance prostate cancer (CRPC), it comprises estradiol, ethinyl estradiol, steroids estrogen agonist, on-steroidal estrogen agonist or its combination of administering therapeutic effective dose.
In one embodiment, the invention provides a kind of reduction and suffer from the method for the free serum testosterone levels in the male subject of castration resistance prostate cancer (CRPC), it comprises formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose.In another embodiment, castration is operation castration.In another embodiment, castration is androgen deprivation.In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, described method is further treated, is suppressed new bone transfer, reduces its incidence of disease, reduces its seriousness or suppress new bone and shift.In another embodiment, described method is further treated, is suppressed soft tissue transfer (internal organ and lymph node) new or that worsen, reduces its incidence of disease, reduces its seriousness or suppress soft tissue new or that worsen and shift.In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts LHRH activator or antagonist.In another embodiment, LHRH activator is leuprorelin acetate.In another embodiment, experimenter has experienced orchiectomy.In another embodiment, experimenter has prostate specific antigen (PSA) level high or that increase.In another embodiment, using of compound can not cause the side effect relevant to androgen-deprivation therapy (ADT).In another embodiment, described method is further treated, is suppressed advanced prostate cancer, reduces its incidence of disease, reduces its seriousness or suppresses advanced prostate cancer.In another embodiment, described method further provides the palliative treatment of advanced prostate cancer.In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.In another embodiment, free serum testosterone is reduced to the level lower than castration.In another embodiment, free serum testosterone is reduced to lower than using LHRH activator or antagonist or the viewed level of operation castration.
In one embodiment, the invention provides a kind of reduction and suffer from the method for the free serum testosterone levels in the male subject of castration resistance prostate cancer (CRPC), it comprises estradiol, ethinyl estradiol, steroids estrogen agonist, on-steroidal estrogen agonist or its combination of administering therapeutic effective dose.
In one embodiment, the invention provides a kind of reduction and suffer from the method for the free serum testosterone percentage (free T%) in the male subject of castration resistance prostate cancer (CRPC), it comprises formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose.In another embodiment, castration is operation castration.In another embodiment, castration is androgen deprivation.In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, described method is further treated, is suppressed new bone transfer, reduces its incidence of disease, reduces its seriousness or suppress new bone and shift.In another embodiment, described method is further treated, is suppressed soft tissue transfer (internal organ and lymph node) new or that worsen, reduces its incidence of disease, reduces its seriousness or suppress soft tissue new or that worsen and shift.In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts LHRH activator or antagonist.In another embodiment, LHRH activator is leuprorelin acetate.In another embodiment, experimenter has experienced orchiectomy.In another embodiment, experimenter has prostate specific antigen (PSA) level high or that increase.In another embodiment, using of compound can not cause the side effect relevant to androgen-deprivation therapy (ADT).In another embodiment, described method is further treated, is suppressed advanced prostate cancer, reduces its incidence of disease, reduces its seriousness or suppresses advanced prostate cancer.In another embodiment, described method further provides the palliative treatment of advanced prostate cancer.In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.In another embodiment, free serum testosterone is reduced to the level lower than castration.In another embodiment, free serum testosterone is reduced to lower than using LHRH activator or antagonist or the viewed level of operation castration.
In one embodiment, the invention provides a kind of reduction and suffer from the method for the free serum testosterone percentage (free T%) in the male subject of castration resistance prostate cancer (CRPC), it comprises estradiol, ethinyl estradiol, steroids estrogen agonist, on-steroidal estrogen agonist or its combination of administering therapeutic effective dose.
In one embodiment, the invention provides a kind of reduction and suffer from the method for the Serum PSA level in the male subject of castration resistance prostate cancer (CRPC), it comprises formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose.In another embodiment, castration is operation castration.In another embodiment, castration is androgen deprivation.In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, described method is further treated, is suppressed new bone transfer, reduces its incidence of disease, reduces its seriousness or suppress new bone and shift.In another embodiment, described method is further treated, is suppressed soft tissue transfer (internal organ and lymph node) new or that worsen, reduces its incidence of disease, reduces its seriousness or suppress soft tissue new or that worsen and shift.In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts LHRH activator or antagonist.In another embodiment, LHRH activator is leuprorelin acetate.In another embodiment, experimenter has experienced orchiectomy.In another embodiment, experimenter has prostate specific antigen (PSA) level high or that increase.In another embodiment, using of compound can not cause the side effect relevant to androgen-deprivation therapy (ADT).In another embodiment, described method is further treated, is suppressed advanced prostate cancer, reduces its incidence of disease, reduces its seriousness or suppresses advanced prostate cancer.In another embodiment, described method further provides the palliative treatment of advanced prostate cancer.In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.In another embodiment, Serum PSA level reduces at least 10% from baseline.In another embodiment, Serum PSA level reduces at least 30% from baseline.In another embodiment, Serum PSA level reduces at least 50% from baseline.In another embodiment, Serum PSA level reduces at least 70% from baseline.In another embodiment, Serum PSA level reduces at least 90% from baseline.
In one embodiment, the invention provides a kind of reduction and suffer from the method for the Serum PSA level in the male subject of castration resistance prostate cancer (CRPC), it comprises estradiol, ethinyl estradiol, steroids estrogen agonist, on-steroidal estrogen agonist or its combination of administering therapeutic effective dose.
In one embodiment, the invention provides a kind of increase and suffer from the method for sex hormone binding globulin (SHBG) level in the male subject of castration resistance prostate cancer (CRPC), it comprises formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose.In another embodiment, castration is operation castration.In another embodiment, castration is androgen deprivation.In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, described method is further treated, is suppressed new bone transfer, reduces its incidence of disease, reduces its seriousness or suppress new bone and shift.In another embodiment, described method is further treated, is suppressed soft tissue transfer (internal organ and lymph node) new or that worsen, reduces its incidence of disease, reduces its seriousness or suppress soft tissue new or that worsen and shift.In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts LHRH activator or antagonist.In another embodiment, LHRH activator is leuprorelin acetate.In another embodiment, experimenter has experienced orchiectomy.In another embodiment, experimenter has prostate specific antigen (PSA) level high or that increase.In another embodiment, using of compound can not cause the side effect relevant to androgen-deprivation therapy (ADT).In another embodiment, described method is further treated, is suppressed advanced prostate cancer, reduces its incidence of disease, reduces its seriousness or suppresses advanced prostate cancer.In another embodiment, described method further provides the palliative treatment of advanced prostate cancer.In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, the invention provides a kind of increase and suffer from the method for sex hormone binding globulin (SHBG) level in the male subject of castration resistance prostate cancer (CRPC), it comprises estradiol, ethinyl estradiol, steroids estrogen agonist, on-steroidal estrogen agonist or its combination of administering therapeutic effective dose.
In one embodiment, the invention provides a kind of reduction and suffer from the method for free serum testosterone levels in the male subject of advanced prostate cancer and/or free serum testosterone percentage (free T%), it comprises formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination with the ADT combined administration treatment effective dose of other form.In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, the ADT of other form refers to LHRH activator.In another embodiment, LHRH activator is leuprorelin acetate.In another embodiment, the ADT of other form refers to lhrh antagonist.In another embodiment, lhrh antagonist is Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2 (degarelix).In another embodiment, experimenter has experienced orchiectomy.In another embodiment, experimenter has prostate specific antigen (PSA) level high or that increase.In another embodiment, using of compound can not cause the side effect relevant to androgen-deprivation therapy (ADT).In another embodiment, described method further provides the palliative treatment of advanced prostate cancer.In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.In another embodiment, free serum testosterone is reduced to the level lower than castration.In another embodiment, free serum testosterone is reduced to lower than using LHRH activator or antagonist or the viewed level of operation castration.
In one embodiment, the invention provides a kind of reduction and suffer from the method for free serum testosterone levels in the male subject of prostate cancer and/or free serum testosterone percentage (free T%), it comprises formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination with selective estrogen receptor modulators (SERM) combined administration treatment effective dose.In another embodiment, prostate cancer is advanced prostate cancer.In another embodiment, prostate cancer is castration resistance prostate cancer (CRPC).In another embodiment, prostate cancer is metastatic castration resistance prostate cancer (mCRPC).In another embodiment, SERM is selected from the group that the following forms: Tamoxifen (tamoxifen), Toremifene (toremifene), Raloxifene (Raloxifene), Clomifene (clomifene), the graceful treasured of cottonrose hibiscus (femarelle), Ormeloxifene (ormeloxifene) and lasofoxifene (lasofoxifene).In another embodiment, SERM is Tamoxifen.In another embodiment, SERM is Raloxifene.In another embodiment, SERM is Toremifene.In another embodiment, SERM is Ormeloxifene.In another embodiment, experimenter has experienced orchiectomy.In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter has prostate specific antigen (PSA) level high or that increase.In another embodiment, using of compound can not cause the side effect relevant to androgen-deprivation therapy (ADT).In another embodiment, described method further provides the palliative treatment of advanced prostate cancer.In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.In another embodiment, free serum testosterone percentage is reduced to lower than approximately 1%.In another embodiment, free serum testosterone percentage is reduced to lower than approximately 0.5%.In another embodiment, free serum testosterone percentage is reduced to lower than approximately 0.4%.In another embodiment, free serum testosterone percentage is reduced to lower than approximately 0.25%.In another embodiment, free serum testosterone percentage is reduced to lower than approximately 0.1%.In another embodiment, free serum testosterone percentage is reduced to lower than approximately 0.05%.In another embodiment, free serum testosterone percentage is reduced to the level lower than castration.In another embodiment, free serum testosterone percentage is reduced to lower than using LHRH activator or antagonist or the viewed level of operation castration.
In one embodiment, the invention provides a kind of reduction and suffer from the method for free serum testosterone levels in the male subject of prostate cancer and/or free serum testosterone percentage (free T%), it comprises estradiol, ethinyl estradiol, steroids estrogen agonist, on-steroidal estrogen agonist or its combination of administering therapeutic effective dose.
In one embodiment, the invention provides a kind of method for suffering from the secondary hormone therapy of blood-serum P SA in the male subject of castration resistance prostate cancer (CRPC) and free serum testosterone levels, it comprises formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose.In another embodiment, castration is operation castration.In another embodiment, castration is androgen deprivation.In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, described method is further treated, is suppressed new bone transfer, reduces its incidence of disease, reduces its seriousness or suppress new bone and shift.In another embodiment, described method is further treated, is suppressed soft tissue transfer (internal organ and lymph node) new or that worsen, reduces its incidence of disease, reduces its seriousness or suppress soft tissue new or that worsen and shift.In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts LHRH activator or antagonist.In another embodiment, LHRH activator is leuprorelin acetate.In another embodiment, experimenter has experienced orchiectomy.In another embodiment, experimenter has prostate specific antigen (PSA) level high or that increase.In another embodiment, using of compound can not cause the side effect relevant to androgen-deprivation therapy (ADT).In another embodiment, described method is further treated, is suppressed advanced prostate cancer, reduces its incidence of disease, reduces its seriousness or suppresses advanced prostate cancer.In another embodiment, described method further provides the palliative treatment of advanced prostate cancer.In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, the invention provides a kind for the treatment of, compacting and suffer from bone dependent event (SRE) in the male subject of castration resistance prostate cancer (CRPC), reduce its incidence of disease, reduce the method that its seriousness or inhibition suffer from the bone dependent event (SRE) in the male subject of castration resistance prostate cancer (CRPC), it comprises formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose.In another embodiment, castration is operation castration.In another embodiment, castration is androgen deprivation.In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, described method is further treated, is suppressed new bone transfer, reduces its incidence of disease, reduces its seriousness or suppress new bone and shift.In another embodiment, described method is further treated, is suppressed soft tissue transfer (internal organ and lymph node) new or that worsen, reduces its incidence of disease, reduces its seriousness or suppress soft tissue new or that worsen and shift.In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts LHRH activator or antagonist.In another embodiment, LHRH activator is leuprorelin acetate.In another embodiment, experimenter has experienced orchiectomy.In another embodiment, experimenter has prostate specific antigen (PSA) level high or that increase.In another embodiment, using of compound can not cause the side effect relevant to androgen-deprivation therapy (ADT).In another embodiment, described method is further treated, is suppressed advanced prostate cancer, reduces its incidence of disease, reduces its seriousness or suppresses advanced prostate cancer.In another embodiment, described method further provides the palliative treatment of advanced prostate cancer.In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
Term " bone dependent event (SRE) " refers to composite end points, and it comprises fracture, pathologic fracture, spinal compression, to the radiation of bone or operation, new bone transfer, bone-loss or its combination.
In one embodiment, using method provided in this article and/or utilizing the bone dependent event of composition treatment provided in this article is fracture, and fracture is pathologic fracture, atraumatic fracture, vertebral fracture, non-vertebral fracture, somatometry of physique fracture or its combination in one embodiment.In some embodiments, fracture can be Fracture Simple, compound fracture, horizontal fracture, greendstick fracture or comminuted fracture.In one embodiment, fracture can be for any bone in health, and fracture is the fracture of any one or more bone, wrist, hand, finger, leg, ankle, foot, toe, hip, clavicle or its combination of arm in one embodiment.
In another embodiment, method provided in this article and/or composition be effective in treatment, prevention, compacting, suppress bone dependent event or reduce the risk of bone dependent event, described bone dependent event as pathologic fracture, spinal compression, hypercalcinemia, bone is ache related or its combination.
In another embodiment, seek by method provided in this article and/or utilize bone dependent event that composition provided in this article is treated to comprise the necessity of bone surgery and/or bone radiation, in some embodiments, bone surgery and/or bone radiation are used for the treatment of the pain being caused by bone injury or neurothlipsis in one embodiment.In another embodiment, seek by method provided in this article and/or utilize bone dependent event that composition provided in this article is treated to comprise the necessity of the variation (comprising the variation of hormonotherapy) of the antitumor therapy in spinal compression or experimenter.In some embodiments, seek by method provided in this article and/or utilize the bone dependent event that composition provided in this article is treated to comprise treatment, compacting, prevention bone transfer or bone-loss, reduce its incidence of disease or postpone its progress or seriousness.In one embodiment, bone-loss can comprise that osteoporosis, sclerotin reduce or its combination.In one embodiment, bone dependent event can comprise any combination of embodiment cited herein.
In one embodiment, the invention provides a kind of reduction and suffer from the method for the level of Bone turnover marker in the male subject of castration resistance prostate cancer (CRPC), it comprises formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose.In another embodiment, castration is operation castration.In another embodiment, castration is androgen deprivation.In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, described method is further treated, is suppressed new bone transfer, reduces its incidence of disease, reduces its seriousness or suppress new bone and shift.In another embodiment, described method is further treated, is suppressed soft tissue transfer (internal organ and lymph node) new or that worsen, reduces its incidence of disease, reduces its seriousness or suppress soft tissue new or that worsen and shift.In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts LHRH activator or antagonist.In another embodiment, LHRH activator is leuprorelin acetate.In another embodiment, experimenter has experienced orchiectomy.In another embodiment, experimenter has prostate specific antigen (PSA) level high or that increase.In another embodiment, using of compound can not cause the side effect relevant to androgen-deprivation therapy (ADT).In another embodiment, described method is further treated, is suppressed advanced prostate cancer, reduces its incidence of disease, reduces its seriousness or suppresses advanced prostate cancer.In another embodiment, described method further provides the palliative treatment of advanced prostate cancer.In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.In another embodiment, Bone turnover marker is C-end peptide (CTX) and/or bone specific alkaline phosphatase.
In one embodiment, the invention provides a kind for the treatment of, compacting and suffer from hot flash in the male subject of castration resistance prostate cancer (CRPC), reduce its incidence of disease, reduce its seriousness, reduce the method that its frequency or inhibition suffer from the hot flash in the male subject of castration resistance prostate cancer (CRPC), it comprises formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose.In another embodiment, castration is operation castration.In another embodiment, castration is androgen deprivation.In another embodiment, CRPC is metastatic CRPC (mCRPC).
In one embodiment, the invention provides a kind of reduction and suffer from the method for the estrogen deficiency related side effects (hot flash, bone-loss, insulin resistance, health form variation, fat increases) in the male subject of advanced prostate cancer or castration resistance prostate cancer, it comprises uses formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination.In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts LHRH activator or antagonist.In another embodiment, LHRH activator is leuprorelin acetate.In another embodiment, castration is operation castration.In another embodiment, castration is androgen deprivation.In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, the male sex is the male sex with operative Modality castration who suffers from advanced prostate cancer or castration resistance prostate cancer.
In another embodiment, described method is further treated, is suppressed new bone transfer, reduces its incidence of disease, reduces its seriousness or suppress new bone and shift.In another embodiment, described method is further treated, is suppressed soft tissue transfer (internal organ and lymph node) new or that worsen, reduces its incidence of disease, reduces its seriousness or suppress soft tissue new or that worsen and shift.In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts LHRH activator or antagonist.In another embodiment, LHRH activator is leuprorelin acetate.In another embodiment, experimenter has experienced orchiectomy.In another embodiment, experimenter has prostate specific antigen (PSA) level high or that increase.In another embodiment, using of compound can not cause the side effect relevant to androgen-deprivation therapy (ADT).In another embodiment, described method is further treated, is suppressed advanced prostate cancer, reduces its incidence of disease, reduces its seriousness or suppresses advanced prostate cancer.In another embodiment, described method further provides the palliative treatment of advanced prostate cancer.In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, the invention provides a kind of reduction and suffer from the method that the suprarenal gland of androgen precurosor in the male subject of castration resistance prostate cancer (CRPC) produces level, it comprises formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose.In another embodiment, castration is operation castration.In another embodiment, castration is androgen deprivation.In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, described method is further treated, is suppressed new bone transfer, reduces its incidence of disease, reduces its seriousness or suppress new bone and shift.In another embodiment, described method is further treated, is suppressed soft tissue transfer (internal organ and lymph node) new or that worsen, reduces its incidence of disease, reduces its seriousness or suppress soft tissue new or that worsen and shift.In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts LHRH activator or antagonist.In another embodiment, LHRH activator is leuprorelin acetate.In another embodiment, experimenter has experienced orchiectomy.In another embodiment, experimenter has prostate specific antigen (PSA) level high or that increase.In another embodiment, using of compound can not cause the side effect relevant to androgen-deprivation therapy (ADT).In another embodiment, described method is further treated, is suppressed advanced prostate cancer, reduces its incidence of disease, reduces its seriousness or suppresses advanced prostate cancer.In another embodiment, described method further provides the palliative treatment of advanced prostate cancer.In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.In another embodiment, prostate gland cancer cell utilizes androgen precurosor to produce testosterone or dihydrotestosterone (DHT).In another embodiment, androgen precurosor is dehydroepiandrosterone sulfate (DHEAS) and/or dehydrobenzene (DHEA).
In one embodiment, " experimenter who suffers from castration resistance prostate cancer " refers to following experimenter: used androgen-deprivation therapy (ADT) to treat, ADT has been responded and current blood-serum P SA>2ng/mL before, or current blood-serum P SA>2ng/mL and represent that the minimum of realizing when carrying out ADT has 25% increase.In another embodiment, although referring to maintain, described term carries out androgen-deprivation therapy, but be diagnosed as there is blood-serum P SA progress experimenter in another embodiment, experimenter has the total testosterone of serum (<50ng/dL) of castration level.The blood-serum P SA while evaluating continuously for twice of experimenter's at least 2 weeks at interval in another embodiment, with rising.In another embodiment, with ADT, experimenter has been carried out to effective treatment.In another embodiment, experimenter has the medical history of blood-serum P SA reaction after ADT starts.In another embodiment, experimenter has treated with ADT and has had initial blood-serum P SA reaction, but now blood-serum P SA>2ng/mL and when carrying out ADT viewed minimum have 25% increase.
Term " blood-serum P SA reaction " refers in one embodiment, before starting ADT, blood-serum P SA value has at least 90% to reduce, <10ng/mL or blood-serum P SA (<0.2ng/mL) that can not detection level at any time, or refer to that in another embodiment blood-serum P SA declines at least 50% from baseline, or refer to that in another embodiment blood-serum P SA declines at least 90% from baseline, or refer to that in another embodiment blood-serum P SA declines at least 30% from baseline, or blood-serum P SA declines at least 10% from baseline in another embodiment.
Term " blood-serum P SA progress " refers in one embodiment, and blood-serum P SA increases by 25% or larger and have 2ng/ml or more definitely increase from minimum; Or in another embodiment, refer to blood-serum P SA>2ng/mL, or >2ng/mL and higher than having 25% increase starting androgen-deprivation therapy (ADT) minimum afterwards.
In another embodiment, term " minimum " refers to the minimum PSA level when patient experiences ADT.
In one embodiment, the invention provides a kind of method that reduces the total serum testosterone levels in male subject, it comprises formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose.In another embodiment, male subject suffers from prostate cancer.In another embodiment, total serum testosterone is reduced to lower than about 100ng/dL.In another embodiment, total serum testosterone is reduced to lower than about 50ng/dL.In another embodiment, total serum testosterone concentration is reduced to lower than about 25ng/dL.In another embodiment, total serum testosterone concentration is reduced to lower than about 10ng/dL.In another embodiment, total serum testosterone concentration is reduced to lower than about 5ng/dL.In another embodiment, total serum testosterone concentration is reduced to lower than about 1ng/dL.In another embodiment, experimenter suffers from castration resistance prostate cancer (CRPC).In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, the invention provides a kind of method that reduces the total serum testosterone levels in male subject, it comprises formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and wherein the reduction of total serum testosterone occurs by the reduction of serum luteinizing hormone (LH) level.In another embodiment, male subject suffers from prostate cancer.In another embodiment, total serum testosterone is reduced to lower than about 100ng/dL.In another embodiment, total serum testosterone is reduced to lower than about 50ng/dL.In another embodiment, total serum testosterone concentration is reduced to lower than about 25ng/dL.In another embodiment, experimenter suffers from castration resistance prostate cancer (CRPC).In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, the invention provides a kind of method that reduces the free level of serum testosterone in male subject, it comprises formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and wherein the reduction of free serum testosterone occurs by the reduction of serum luteinizing hormone (LH) level.In another embodiment, male subject suffers from prostate cancer.In another embodiment, experimenter suffers from castration resistance prostate cancer (CRPC).In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, the invention provides a kind of method that reduces the total serum testosterone levels in male subject, it comprises formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and wherein the reduction of total serum testosterone is independent of the reduction of serum luteinizing hormone (LH) level.In another embodiment, male subject suffers from prostate cancer.In another embodiment, total serum testosterone is reduced to lower than about 100ng/dL.In another embodiment, total serum testosterone is reduced to lower than about 50ng/dL.In another embodiment, total serum testosterone concentration is reduced to lower than about 25ng/dL.In another embodiment, experimenter suffers from castration resistance prostate cancer (CRPC).In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, the invention provides a kind of method that reduces the free level of serum testosterone in male subject, it comprises formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose, and wherein the reduction of free level of serum testosterone is independent of the reduction of serum luteinizing hormone level.In another embodiment, male subject suffers from prostate cancer.In another embodiment, experimenter suffers from castration resistance prostate cancer (CRPC).In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, the invention provides the method for the total serum testosterone levels reducing in male subject, free level of serum testosterone or free serum testosterone percentage (free T%), wherein said male subject suffers from prostate cancer.In another embodiment, described experimenter suffers from advanced prostate cancer.In another embodiment, experimenter suffers from castration resistance prostate cancer (CRPC).In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
Term " free serum testosterone percentage (free T%) " refers in one embodiment, and free level of serum testosterone (pg/mL) is multiplied by 100 [free T (pg/mL)/total T (pg/mL) * 100] again divided by total serum testosterone levels (pg/mL).
In one embodiment, the reduction of serum testosterone concentration is reversible and is back to baseline values after with compounds for treating of the present invention.
In another embodiment, according to Figure 23 and embodiment 10 serum testosterone concentration, after with compound IV treatment, be reversible.
In one embodiment, the invention provides the method that reduces the total serum testosterone levels in male subject, it comprises formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose.In another embodiment, total serum testosterone is reduced to lower than about 100ng/dL.In another embodiment, total serum testosterone is reduced to lower than about 50ng/dL.In another embodiment, total serum testosterone is reduced to lower than about 25ng/dL.In another embodiment, total serum testosterone is reduced to lower than about 75ng/dL.In another embodiment, total serum testosterone is reduced between about 75ng/dL to 100ng/dL.In another embodiment, total serum testosterone is reduced between about 50ng/dL to 75ng/dL.In another embodiment, total serum testosterone is reduced between about 40ng/dL to 50ng/dL.In another embodiment, total serum testosterone concentration is reduced between about 25ng/dL to 50ng/dL.In another embodiment, total serum testosterone is reduced between about 40ng/dL to 60ng/dL.In another embodiment, total serum testosterone is reduced between about 10ng/dL to 50ng/dL.In another embodiment, total serum testosterone is reduced between about 10ng/dL to 25ng/dL.In another embodiment, total serum testosterone is reduced between about 1ng/dL to 25ng/dL.In another embodiment, total serum testosterone is reduced between about 1ng/dL to 10ng/dL.In another embodiment, total serum testosterone is reduced between about 0.1ng/dL to 1ng/dL.In another embodiment, total serum testosterone is reduced between about 0.1ng/dL to 10ng/dL.In another embodiment, experimenter suffers from castration resistance prostate cancer (CRPC).In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, the method that the invention provides the free serum testosterone percentage (free T%) reducing in male subject, it comprises formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose.In another embodiment, free serum testosterone percentage (free T%) is reduced to lower than approximately 1%.In another embodiment, free serum testosterone percentage (free T%) is reduced to lower than approximately 0.5%.In another embodiment, free serum testosterone percentage (free T%) is reduced to lower than approximately 0.25%.In another embodiment, free serum testosterone percentage (free T%) is reduced to lower than approximately 0.05%.In another embodiment, experimenter suffers from castration resistance prostate cancer (CRPC).In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
Testosterone can be measured as " free " (that is, bioavailable with unconjugated) or be serum levels " total " (comprise combined with protein with disabled percentage).In one embodiment, total serum testosterone comprises the testosterone of free testosterone and combination.
Within 40 years old, the above male sex without prostate cancer proves low testosterone levels, has the total testosterone levels that is less than 250ng/dL (<8.7nmol/L) or the free testosterone level that is less than 0.75ng/dL (<0.03nmol/L).Method of the present invention provides a kind of method that reduces level of serum testosterone.In one embodiment, the method providing reduces total serum testosterone.In another embodiment, the method providing reduces free serum testosterone.
In one embodiment, method of the present invention provides a kind of and is independent of the reduction of luteinizing hormone (LH) level or by reduction, suffers from the method that LH level in the male subject of prostate cancer reduces total serum and/or free testosterone level.In another embodiment, the variation of testosterone levels should be from the reduction for the treatment of level before.In another embodiment, total serum testosterone levels is reduced to lower than 100ng/dL.In another embodiment, total serum testosterone is reduced to lower than 50ng/dL.In another embodiment, total serum testosterone is reduced to lower than 25ng/dL.In another embodiment, free testosterone level is reduced to lower than 2ng/dL.In another embodiment, free testosterone level is reduced to lower than 1ng/dL.In another embodiment, free testosterone level is reduced to lower than 0.5ng/dL.In another embodiment, free testosterone level is reduced to lower than 0.25ng/dL.In another embodiment, experimenter suffers from castration resistance prostate cancer (CRPC).In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
The method of measuring free level of serum testosterone and total serum testosterone levels comprises by blood testing monitors testosterone levels in treatment phase process.Total testosterone is the combination that is bonded to circulation testosterone with the free/unconjugated hormone of carrier protein (albumin, SHBG, corticosteroid-binding globulin, transferrins).Total testosterone levels may be subject to the impact of several factors, and described factor is included in level, age, obesity and the interference relevant to normally used method of testing of the protein in the blood that transports hormone in health.
The method of using simulation tracer to be available for measuring free testosterone (FT) can be complicated (free testosterone of equilibrium dialysis and calculating (CFT)) or simple (business FT kit " Coat-A-Count ").In another embodiment, the measurement of total testosterone and free testosterone serum levels can for example, realize by the free testosterone (CFT) of measuring total testosterone and SHBG (, Irma-Count, DPC) and then calculate simultaneously.In another embodiment, the measurement of total testosterone and free testosterone is the knowledge according to those skilled in the art.
In one embodiment, the invention provides a kind of method that reduces the total serum testosterone levels in male subject, free level of serum testosterone or free serum testosterone percentage (free T%), it comprises the ADT of one or more other forms and the combination of formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose.In another embodiment, the reduction that serum luteinizing hormone (LH) level is passed through in reduction total or free serum testosterone occurs.In another embodiment, reduce the reduction that total or free level of serum testosterone is independent of serum luteinizing hormone level.In another embodiment, experimenter suffers from castration resistance prostate cancer (CRPC).In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, the invention provides a kind of method that reduces the total serum testosterone levels in male subject, free level of serum testosterone or free serum testosterone percentage (free T%), it comprises one or more selective estrogen receptor modulators (SERM) of administering therapeutic effective dose and the combination of formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination.In another embodiment, experimenter suffers from advanced prostate cancer.In another embodiment, experimenter suffers from castration resistance prostate cancer (CRPC).In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, SERM selects the group that free the following forms: Tamoxifen, Toremifene, Raloxifene, Clomifene, the graceful treasured of cottonrose hibiscus, Ormeloxifene and lasofoxifene.In another embodiment, SERM is Tamoxifen.In another embodiment, SERM is Raloxifene.In another embodiment, SERM is Toremifene.In another embodiment, SERM is Ormeloxifene.In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, a kind of method that the invention provides treatment, compacting castration resistance prostate cancer (CRPC) and its symptom, reduces its incidence of disease, reduces its seriousness or suppress its progress or increase the male sex's who suffers from castration resistance prostate cancer survival rate, it comprises the ADT of one or more other forms and the combination of formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose.In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, the invention provides a kind of reduction and suffer from the method for the Serum PSA level in the male subject of castration resistance prostate cancer (CRPC), it comprises the ADT of one or more other forms and the combination of formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose.In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, the invention provides a kind of reduction and suffer from free testosterone level, the percentage of free serum testosterone and/or the method for blood-serum P SA in the male subject of advanced prostate cancer, it comprises the ADT of one or more other forms and the combination of formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose.In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
Method of the present invention comprises the combination of using estrogen receptor ligands and the compounds of this invention.In one embodiment, estrogen receptor ligands includes but not limited to selective estrogen receptor modulators (SERM).The example of SERM includes but not limited to: Tamoxifen, Toremifene, Raloxifene, Clomifene, the graceful treasured of cottonrose hibiscus, Ormeloxifene and lasofoxifene.
Method of the present invention comprises the combination of ADT and the compounds of this invention of using other form.In one embodiment, the ADT of other form comprises LHRH activator.In another embodiment, LHRH activator comprises leuprorelin acetate (US5,480,656; US5,575,987; 5,631,020; 5,643,607; 5,716,640; 5,814,342; 6,036,976, described document is all incorporated to herein by reference) or goserelin acetate (US7,118,552; 7,220,247; 7,500,964, described document is all incorporated to herein by reference).In one embodiment, the ADT of other form comprises lhrh antagonist.In another embodiment, lhrh antagonist comprises Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2.In one embodiment, the ADT of other form comprises antiandrogen.In another embodiment, antiandrogen comprises Bicalutamide (bicalutamide), Flutamide (flutamide), Finasteride (finasteride), dutasteride (dutasteride), the assorted Shandong amine (enzalutamide) of grace, Nilutamide (nilutamide), chlormadinone (chlormadinone) or its any combination.In one embodiment, the ADT of other form comprises bilateral orchidectomy.
In one embodiment, method of the present invention comprises antiandrogen and the compound of the present invention of administering therapeutic effective dose.In one embodiment, method of the present invention comprises LHRH activator and the compound of the present invention of administering therapeutic effective dose.In one embodiment, method of the present invention comprises antiandrogen, LHRH activator and the compound of the present invention of administering therapeutic effective dose.In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, the invention provides a kind of object for producing androgen-deprivation therapy (ADT), the reduction of suffering from luteinizing hormone (LH) level in the male subject of prostate cancer by reduction or being independent of luteinizing hormone level reduces the method for total serum testosterone levels, free level of serum testosterone and/or free serum testosterone percentage (free T%), and it comprises formula IA, I to the XII compound of administering therapeutic effective dose.In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.In another embodiment, prostate cancer is castration resistance prostate cancer (CRPC).In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).
In another embodiment, the invention provides a kind of method of the androgen-deprivation therapy (ADT) for experimenter, it comprises formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose.In another embodiment, described experimenter suffers from prostate cancer.In another embodiment, prostate cancer is castration resistance prostate cancer (CRPC).In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).
In another embodiment, ADT be used for the treatment of prostate cancer, for postponing the progress of prostate cancer or for preventing and/or treating the recurrence of prostate cancer.In another embodiment, prostate cancer is castration resistance prostate cancer (CRPC).In another embodiment, CRPC is metastatic CRPC (mCRPC).
In one embodiment, the invention provides a kind of method for the treatment of prostate cancer or postponing the progress of prostate cancer, it comprises uses compound of the present invention.In one embodiment, the invention provides a kind of method that prevents and/or treats the recurrence of prostate cancer, it comprises uses compound of the present invention.In another embodiment, prostate cancer is castration resistance prostate cancer (CRPC).In another embodiment, CRPC is metastatic CRPC (mCRPC).
In one embodiment, the invention provides a kind of method of survival rate that increase suffers from the experimenter of prostate cancer, advanced prostate cancer, castration resistance prostate cancer or metastatic castration resistance prostate cancer, it comprises uses compound of the present invention.In another embodiment, with p-GLU-HIS-TRP-SER-TYR-D-TRP-LEU-ARG-PRO-GLY-NH2, invertibity antiandrogen (as the assorted Shandong of Bicalutamide, Flutamide or grace amine), antiestrogenic, cancer therapy drug, 5-alpha reductase inhibitor, aromatase inhibitor, progestational hormone, SARM (SARM) or the medicament combined administration compound of the present invention that works by other nuclear hormone receptor.In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, the invention provides and a kind ofly by the reduction that reduces LH level or be independent of LH level, treated prostate cancer and reduced the method for total serum testosterone levels and/or free level of serum testosterone, it comprises uses formula IA, I to XII compound.In another embodiment, administered compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.In another embodiment, prostate cancer is castration resistance prostate cancer (CRPC).In another embodiment, CRPC is metastatic CRPC (mCRPC).
Androgen-deprivation therapy not only reduces testosterone, and estrogen level is also lower, because oestrogenic hormone derives from the aromatization of testosterone.The estrogen deficiency of androgen-deprivation therapy induction causes significant side effect, described side effect comprises that hot flash, gynecomastia and mastalgia, bone-loss, bone mass and intensity decline, osteoporosis, sclerotin reduce, and mortality is fractured, unfavorable lipid changes and higher angiocardiopathy and miocardial infarction, sexual anesthesia, impotence, muscle quality consumption lost (muscle reduces disease), fatigue, cognition dysfunction and depression and other emotional change.
In other embodiments, the invention provides a kind of method of any disease, illness or symptom that treatment is relevant to ADT.In other embodiments, the invention provides a kind of method of depriving relevant any disease, illness or symptom to testosterone for the treatment of.Every kind of disease, illness or symptom represent independent embodiment of the present invention.
In one embodiment, the invention provides a kind of total serum testosterone levels reducing in male subject, the method of free level of serum testosterone and/or free serum testosterone percentage (free T%), it comprises the formula IA of administering therapeutic effective dose, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination, wherein saidly use described formula IA, I to XII compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combined therapy, prevention, suppress the side effect relevant to androgen-deprivation therapy (ADT), reduce the side effect that its incidence of disease or inhibition are relevant to androgen-deprivation therapy (ADT), in order to avoid its generation, wherein said experimenter suffers from prostate cancer.In another embodiment, reducing total or free level of serum testosterone is by reducing LH level or being independent of the reduction of LH level.In another embodiment, experimenter suffers from castration resistance prostate cancer (CRPC).In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, using compound of the present invention suppresses the typical side effects relevant to traditional androgen-deprivation therapy (ADT), reduces the typical side effects that its incidence of disease, inhibition or treatment are relevant with traditional androgen-deprivation therapy (ADT), in order to avoid its generation.In another embodiment, experimenter suffers from prostate cancer.In another embodiment, prostate cancer is castration resistance prostate cancer (CRPC).In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
This prevention of side effect and/or reduction are with respect to placebo or control group and discuss.In one embodiment, the typical side effects relevant to traditional androgen-deprivation therapy (ADT) comprises the fracture that hot flash, gynecomastia, BMD reduce and increase.In another embodiment, use the hot flash generation that compound prevention of the present invention will be found as used the androgen-deprivation therapy (ADT) of traditional form.In another embodiment, use the gynecomastia generation that compound prevention of the present invention will be found as used the androgen-deprivation therapy (ADT) of traditional form.In another embodiment, use BMD reduction (BMD) generation that compound prevention of the present invention will be found as used the androgen-deprivation therapy (ADT) of traditional form.In another embodiment, use the fracture generation of the increase that compound of the present invention prevents as the androgen-deprivation therapy (ADT) of use traditional form will be found.In another embodiment, fracture refers to pathologic fracture, atraumatic fracture, vertebral fracture, non-vertebral fracture, new somatometry of physique fracture, clinical fracture or its combination.
In one embodiment, use compound of the present invention and reduce total serum testosterone, and can not cause that the typical side effects relevant to traditional androgen-deprivation therapy (ADT) occurs.In another embodiment, experimenter suffers from prostate cancer.In another embodiment again, experimenter suffers from advanced prostate cancer.In another embodiment, experimenter suffers from castration resistance prostate cancer (CRPC).In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, the typical side effects relevant to traditional androgen-deprivation therapy (ADT) comprises the fracture that hot flash, gynecomastia, BMD reduce and increase.In another embodiment, the typical side effects relevant to traditional ADT comprises that body fat increases.In another embodiment, using compound of the present invention can not cause as used the hot flash that the androgen-deprivation therapy (ADT) of traditional form will be found to occur.In another embodiment, using compound of the present invention can not cause as used the gynecomastia that the androgen-deprivation therapy (ADT) of traditional form will be found to occur.In another embodiment, using compound of the present invention can not cause as used the BMD reduction (BMD) that the androgen-deprivation therapy (ADT) of traditional form will be found to occur.In another embodiment, use the fracture generation that compound of the present invention can not cause the increase that will find as the androgen-deprivation therapy (ADT) of use traditional form.In another embodiment, the fracture of increase is pathologic fracture, atraumatic fracture, vertebral fracture, non-vertebral fracture, new somatometry of physique fracture, clinical fracture or its combination.In another embodiment again, use compound of the present invention and can not cause that the body fat as used the androgen-deprivation therapy (ADT) of traditional form to find increases generation.In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, use compound of the present invention and reduce free testosterone level, and can not cause that the typical side effects relevant to traditional androgen-deprivation therapy (ADT) occurs.In another embodiment, experimenter suffers from prostate cancer.In another embodiment again, experimenter suffers from advanced prostate cancer.In another embodiment, experimenter suffers from castration resistance prostate cancer (CRPC).In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, use compound of the present invention and reduce free testosterone percentage (free T%), and can not cause that the typical side effects relevant to traditional androgen-deprivation therapy (ADT) occurs.In another embodiment, experimenter suffers from prostate cancer.In another embodiment again, experimenter suffers from advanced prostate cancer.In another embodiment, experimenter suffers from castration resistance prostate cancer (CRPC).In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, experimenter further accepts androgen-deprivation therapy (ADT).In another embodiment, compound is compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, term " hot flash " refers to the top of health or whole unexpected hotness, and face and neck flush occur erythema, perspire in a large number, shiver with cold etc. on chest, the back of the body and arm.
In one embodiment, term " gynecomastia " refers to the optimum increase by the caused male breast of hyperplasia of the body of gland composition of breast, its may with or may not be associated with pain.Gynecomastia is defined by the existence of the rubber-like of extending with one heart from nipple or hard agglomerate clinically.The symptom that is called as false Gynecomastia (pseudogynecomastia) or fatty Gynecomastia (lipomastia) is characterised in that fat deposition and without glandular hyperplasia.Although Gynecomastia is bilateral normally, it can be one-sided.
In one embodiment, method of the present invention is for treating by reducing testosterone the male sex who suffers from prostate cancer or advanced prostate cancer or castration resistance prostate cancer (CRPC) or metastatic castration resistance prostate cancer (mCRPC), and also do not cause bone-loss and hot flash simultaneously.In one embodiment, method of the present invention suffers from the male sex of prostate cancer or advanced prostate cancer or castration resistance prostate cancer (CRPC) or metastatic castration resistance prostate cancer (mCRPC) for treatment, and does not also cause bone-loss, gynecomastia and hot flash simultaneously.
Compound IV can not increase the propagation of external prostatic epithelium cancer cell.In mechanism, compound IV provides several key advantages that are better than existing therapy (as gonadotropin-releasing hormone (GRH) (GnRH) activator and GnRH antagonist).Compound IV has specificity to estrogen receptor, and oral biology is available in rat, dog, monkey and people.Compare with GnRH antagonist with the GnRH activator that causes hot flash and significant bone-loss and increase the risk of fracture, compound IV weakens the hot flash (embodiment 14) of morphine abstinence syndrome induction in rat, and in the distal femoral of rat, maintain trabecular bone quality and BMD completely, even if farthest suppressing under the dosage of LH and serum testosterone.(embodiment 11).
In another embodiment, method of the present invention is utilized Compound I A, I to XII, wherein said compound has the potentiality of minimizing testosterone (the main stimulus of carcinoma of prostate), and also can not cause some side effect simultaneously, as common bone-loss and the hot flash of current androgen-deprivation therapy (ADT) by prostate cancer.
In another embodiment, table 8 (embodiment 11) below proves by administered compound IV and reduces testosterone and can not cause bone-loss.
In one embodiment, method of the present invention for by using formula IA, I to XII compound reduces testosterone levels, thereby further treat advanced prostate cancer.In another embodiment, by administered compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, method of the present invention for by using formula IA, I to XII compound reduces testosterone levels, thereby further treat castration resistance prostate cancer.In another embodiment, by administered compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, method of the present invention for by using formula IA, I to XII compound reduces testosterone levels, thereby further treat metastatic castration resistance prostate cancer (mCRPC).In another embodiment, by administered compound IV.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, method of the present invention for by using formula IA, I to XII compound reduces testosterone levels, thereby further suppress advanced prostate cancer, reduce its incidence of disease, reduce its seriousness or suppress advanced prostate cancer.In another embodiment, method of the present invention is for reducing testosterone levels by administered compound IV, thereby further suppresses advanced prostate cancer, reduces its incidence of disease, reduces its seriousness or suppress advanced prostate cancer.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, method of the present invention for by using formula IA, I to XII compound reduces testosterone levels, thereby further provide advanced prostate cancer, the palliative treatment of CRPC or mCRPC.In another embodiment, method of the present invention is for reducing testosterone levels by using formula IV compound, thereby the palliative treatment of advanced prostate cancer is further provided.In another embodiment, compound be with every day 125mg dosage use.In another embodiment, compound be with every day 250mg dosage use.In another embodiment, compound be with every day 500mg dosage use.
In one embodiment, method of the present invention is for treatment advanced prostate cancer.In another embodiment, method of the present invention is for suppressing advanced prostate cancer, reduce its incidence of disease, reduce its seriousness or suppressing advanced prostate cancer.In one embodiment, method of the present invention is for the palliative treatment of advanced prostate cancer.In another embodiment, the present invention is directed to compacting advanced prostate cancer.In another embodiment, the present invention is directed to the incidence of disease that reduces advanced prostate cancer.In another embodiment, the present invention is directed to the seriousness that reduces advanced prostate cancer.In another embodiment, the present invention is directed to inhibition advanced prostate cancer, it comprises uses compound of the present invention.
In one embodiment, method of the present invention is for treatment castration resistance prostate cancer.In one embodiment, method of the present invention is for suppressing castration resistance prostate cancer, reduce its incidence of disease, reduce its seriousness or suppressing castration resistance prostate cancer.In one embodiment, method of the present invention is for the palliative treatment of castration resistance prostate cancer.In another embodiment, the present invention is directed to compacting castration resistance prostate cancer.In another embodiment, the present invention is directed to the incidence of disease that reduces castration resistance prostate cancer.In another embodiment, the present invention is directed to the seriousness that reduces castration resistance prostate cancer.In another embodiment, the present invention is directed to and suppress castration resistance prostate cancer.In another embodiment, the present invention is directed to the survival rate that increases the experimenter who suffers from castration resistance prostate cancer.In another embodiment, method of the present invention is utilized formula IA, I to XII compound.In another embodiment, method of the present invention is utilized compound IV.In another embodiment, method of the present invention is utilized the combination of formula IA, I to XII compound and LHRH activator.In another embodiment, method of the present invention is utilized the combination of compound IV and LHRH activator.In another embodiment, method of the present invention is utilized compound IV and leuprorelin acetate combination.In another embodiment, method of the present invention is utilized formula IA, I to XII compound and leuprorelin acetate combination.In another embodiment, method of the present invention is utilized the combination of formula IA, I to XII compound and lhrh antagonist.In another embodiment, method of the present invention is utilized the combination of compound IV and lhrh antagonist.In another embodiment, method of the present invention is utilized the combination of compound IV and Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2.In another embodiment, method of the present invention is utilized the combination of formula IA, I to XII compound and Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2.In another embodiment, method of the present invention is utilized the combination of formula IA, I to XII compound and antiandrogen.In another embodiment, method of the present invention is utilized the combination of compound IV and antiandrogen.
In one embodiment, method of the present invention is for treatment metastatic castration resistance prostate cancer.In one embodiment, method of the present invention is for suppressing metastatic castration resistance prostate cancer, reduce its incidence of disease, reduce its seriousness or suppressing metastatic castration resistance prostate cancer.In one embodiment, method of the present invention is for the palliative treatment of metastatic castration resistance prostate cancer.In another embodiment, the present invention is directed to compacting metastatic castration resistance prostate cancer.In another embodiment, the present invention is directed to the incidence of disease that reduces metastatic castration resistance prostate cancer.In another embodiment, the present invention is directed to the seriousness that reduces metastatic castration resistance prostate cancer.In another embodiment, the present invention is directed to and suppress metastatic castration resistance prostate cancer.In another embodiment, the present invention is directed to the survival rate that increases the experimenter who suffers from metastatic castration resistance prostate cancer.In another embodiment, method of the present invention is utilized formula IA, I to XII compound.In another embodiment, method of the present invention is utilized compound IV.In another embodiment, method of the present invention is utilized the combination of formula IA, I to XII compound and LHRH activator.In another embodiment, method of the present invention is utilized the combination of compound IV and LHRH activator.In another embodiment, method of the present invention is utilized compound IV and leuprorelin acetate combination.In another embodiment, method of the present invention is utilized formula IA, I to XII compound and leuprorelin acetate combination.In another embodiment, method of the present invention is utilized the combination of formula IA, I to XII compound and lhrh antagonist.In another embodiment, method of the present invention is utilized the combination of compound IV and lhrh antagonist.In another embodiment, method of the present invention is utilized the combination of compound IV and Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2.In another embodiment, method of the present invention is utilized the combination of formula IA, I to XII compound and Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2.In another embodiment, method of the present invention is utilized the combination of formula IA, I to XII compound and antiandrogen.In another embodiment, method of the present invention is utilized the combination of compound IV and antiandrogen.
In another embodiment, the present invention is directed to the survival rate that increases the experimenter who suffers from advanced prostate cancer, CRPC or mCRPC.In another embodiment, method of the present invention is utilized formula IA, I to XII compound.In another embodiment, method of the present invention is utilized the combination of formula IA, I to XII compound and LHRH activator.In another embodiment, method of the present invention is utilized formula IA, I to XII compound and leuprorelin acetate combination.In another embodiment, method of the present invention is utilized the combination of formula IA, I to XII compound and lhrh antagonist.In another embodiment, method of the present invention is utilized the combination of compound IV and lhrh antagonist.In another embodiment, method of the present invention is utilized the combination of compound IV and Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2.In another embodiment, method of the present invention is utilized the combination of formula IA, I to XII compound and Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2.In another embodiment, method of the present invention is utilized the combination of formula IA, I to XII compound and antiandrogen.In another embodiment, method of the present invention is utilized the combination of compound IV and antiandrogen.
In another embodiment, the present invention is directed to the survival rate that increases the experimenter who suffers from advanced prostate cancer, CRPC or mCRPC.In another embodiment, method of the present invention is utilized compound IV.In another embodiment, method of the present invention is utilized the combination of compound IV and LHRH activator.In another embodiment, method of the present invention is utilized compound IV and leuprorelin acetate combination.In another embodiment, method of the present invention is utilized the combination of compound IV and lhrh antagonist.In another embodiment, method of the present invention is utilized the combination of compound IV and Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2.
Term " advanced prostate cancer " refers to and is derived from prostate and has extensively been transferred to prostate (as surrounding tissue) in addition to comprising seminal vesicle, lymphonodi pelvini or bone or to the metastatic cancer of the other parts of health.Prostate cancer pathology is by the pernicious order from 1 to 5 increasing, to carry out classification with Gleason (Gleason) classification.In another embodiment, the patient who has from the PD of prostate cancer and/or dead remarkable risk should be included among described definition, and suffers from any patient that disease grade is low to moderate the cancer outside capsula prostatica of IIB and obviously suffer from " late period " disease.
The male sex who suffers from advanced prostate cancer often receives treatment to block androgenic generation, and androgen is the androgenic hormone that can help tumor of prostate growth.Yet, the ability that the final development of prostate cancer at first anti androgenic therapy being responded is grown in without androgenic situation.Described cancer be often called as hormone refractory, do not rely on androgenic or castration resistance.
In one embodiment, advanced prostate cancer is castration resistance prostate cancer.
Term " castration resistance prostate cancer " (CRPC) refer to be considered to hormone refractory, hormone is untreated, it is androgenic or chemical or operation castration resistance not rely on.
In another embodiment, castration resistance prostate cancer (CRPC) carries out although be the advanced prostate cancer that ADT and/or operation castration still develop.In another embodiment, ADT refers to and comprises leuprorelin acetate treatment.
In one embodiment, castration resistance prostate cancer is defined as following prostate cancer: although carry out before operation castration, continue to treat with following thing the healthy prostate cancer that still continues progress or worsen or adversely affect patient: GuRH-A (for example, Leuprorelin) or antagonist (Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2), antiandrogen (for example, Bicalutamide, Flutamide, the assorted Shandong of grace amine, ketoconazole (ketoconazole), aminoglutethimide), chemotherapeutant (for example, docetaxel, taxol, he fills in kappa, adriamycin, mitoxantrone, Estramustine, cyclophosphamide), inhibitors of kinases (Imatinib or Gefitinib ) or other prostate cancer therapy (for example, vaccine (western Pu Lusaier-T (sipuleucel-T) gVAX etc.), herbal medicine (PC-SPES) and lyase inhibitors (abiraterone), as the deterioration of the size of the increase of the prostate specific antigen by that increase or higher (PSA) serum levels, transfer, bone transfer, pain, lymph node involvement, tumor growth or blood serum designated object, prognosis diagnostic marker or status of patient proved.In another embodiment, castration resistance prostate cancer is defined as the untreated prostate cancer of hormone.
Many early prostate cancers need androgen to grow, but advanced prostate cancer is often not rely on androgenic or hormone is untreated.In suffering from the male sex of castration resistance prostate cancer, tumour cell can have in the situation that the ability that does not exist androgen (promoting the growth of male sex character and the hormone maintaining) to grow.
In one embodiment, term " androgen-deprivation therapy " (ADT) or " traditional androgen-deprivation therapy " for orchiectomy (operation castration), wherein surgeon removes testis.In another embodiment, term " androgen-deprivation therapy " or " traditional androgen-deprivation therapy " are for using luteinising hormone-releasing hormo (LHRH) analog: these medicines reduce the amount of the testosterone being produced by testis.Example at the obtainable p-GLU-HIS-TRP-SER-TYR-D-TRP-LEU-ARG-PRO-GLY-NH2 of the U.S. comprises Leuprorelin goserelin triptorelin and Histrelin in another embodiment, term " androgen-deprivation therapy " or " traditional androgen-deprivation therapy " are for using antiandrogen: antiandrogen blocking-up health is used any androgenic ability.Even, after orchiectomy or with in p-GLU-HIS-TRP-SER-TYR-D-TRP-LEU-ARG-PRO-GLY-NH2 therapeutic process, still by suprarenal gland, produce a small amount of androgen.The example of antiandrogen medicine comprises the assorted Shandong of grace amine, Flutamide bicalutamide and Nilutamide in another embodiment, term " androgen-deprivation therapy " or " traditional androgen-deprivation therapy " are for using luteinising hormone-releasing hormo (LHRH) antagonist, as abarelix or Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2 (in 2008, by FDA approval, being used for the treatment of advanced prostate cancer).In another embodiment, term " androgen-deprivation therapy " or " traditional androgen-deprivation therapy " are for using 5α-reductase inhibitor, as Finasteride and dutasteride 5α-reductase inhibitor blocking-up health changes into testosterone the ability that has more active androgen 5α-dihydrotestosterone (DHT).In another embodiment, term " androgen-deprivation therapy " or " traditional androgen-deprivation therapy " are for using the biosynthetic inhibitor of testosterone as ketoconazole in another embodiment, term " androgen-deprivation therapy " or " traditional androgen-deprivation therapy " are for using oestrogenic hormone as diethylstilbestrol or 17 beta estradiols.In another embodiment, term " androgen-deprivation therapy " or " traditional androgen-deprivation therapy " are for using 17 α-hydroxylase/C17, and 20 lyases (CYP17A1) inhibitor is as abiraterone
In one embodiment, method of the present invention for treatment, compacting experimenter's prostate cancer, reduce its incidence of disease, reduce its seriousness, suppress experimenter prostate cancer, provide experimenter prostate cancer palliative treatment or increase its survival rate.In one embodiment, method of the present invention for treatment, compacting experimenter's advanced prostate cancer, reduce its incidence of disease, reduce its seriousness, suppress advanced prostate cancer in experimenter, the palliative treatment of the advanced prostate cancer in experimenter is provided or increases the method for its survival rate.In one embodiment, method of the present invention is for treating, suppress castration resistance prostate cancer, reduce its incidence of disease, reduce its seriousness, suppress castration resistance prostate cancer, the palliative treatment of castration resistance prostate cancer being provided or increasing its survival rate.In one embodiment, method of the present invention is for treating, suppress metastatic castration resistance prostate cancer, reduce its incidence of disease, reduce its seriousness, suppress metastatic castration resistance prostate cancer, the palliative treatment of metastatic castration resistance prostate cancer being provided or increasing its survival rate.In another embodiment, experimenter has prostate specific antigen (PSA) level high or that increase.
In one embodiment, the level that is considered to normal prostate specific antigen (PSA) is age-dependent.In one embodiment, the level that is considered to normal prostate specific antigen (PSA) depends on the prostatic size of male subject.In one embodiment, the PSA level in the scope between 2.5 to 10ng/mL is considered to " the high value in limit ".In another embodiment, the PSA level higher than 10ng/mL is considered to " high ".
In one embodiment, rate of change or " PSA speed " are high.In one embodiment, be greater than rate of change or " the PSA speed " of 0.75/ and be considered to high.
In one embodiment, the present invention is directed to the experimenter that treatment has PSA level high or that increase, it comprises uses compound of the present invention.In one embodiment, although although the present invention is directed to treatment is carrying out ADT or having the history, operation castration of ADT or with antiandrogen and/or LHRH agonist treatment, but still there is the experimenter of PSA level high or increase.In another embodiment, treatment utilizes compound of the present invention.In another embodiment, treatment utilizes compound IV.
In one embodiment, the present invention is directed to the method that reduces prostate specific antigen (PSA) level in experimenter, it comprises uses compound of the present invention.In one embodiment, the present invention is directed to the method that reduces prostate specific antigen (PSA) level in experimenter, it comprises uses formula IA, I to XII compound.In another embodiment, by administered compound IV.In one embodiment, the present invention is directed to the method for prostate specific antigen (PSA) level in a kind of experimenter of reduction, it comprises and LHRH activator combined administration formula IA, I to XII compound.In another embodiment, with LHRH activator combined administration compound IV.In one embodiment, the present invention is directed to the method for prostate specific antigen (PSA) level in a kind of experimenter of reduction, it comprises and lhrh antagonist combined administration formula IA, I to XII compound.In another embodiment, with lhrh antagonist combined administration compound IV.In one embodiment, the present invention is directed to the method for prostate specific antigen (PSA) level in a kind of experimenter of reduction, it comprises and leuprorelin acetate combined administration formula IA, I to XII compound.In another embodiment, with leuprorelin acetate combined administration compound IV.In one embodiment, the present invention is directed to the method for prostate specific antigen (PSA) level in a kind of experimenter of reduction, it comprises and Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2 combined administration formula IA, I to XII compound.In another embodiment, with Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2 combined administration compound IV.In another embodiment, experimenter suffers from advanced prostate cancer.In another embodiment, experimenter suffers from castration resistance prostate cancer (CRPC).In another embodiment, CRPC is metastatic CRPC (mCRPC).In another embodiment, experimenter was lost efficacy for androgen-deprivation therapy (ADT).In another embodiment, compound IV be with every day 125mg dosage use.In another embodiment, compound IV be with every day 250mg dosage use.In another embodiment, compound IV be with every day 500mg dosage use.
In one embodiment, thus the invention provides the method for the treatment of castration resistance prostate cancer by the chemotherapy that compound of the present invention needs to reduce.
In one embodiment, the invention provides a kind for the treatment of, compacting chemotherapy resistance prostate cancer, reduce its incidence of disease, reduce its seriousness, increase its survival rate or suppress the method for chemotherapy resistance prostate cancer.In another embodiment, chemotherapy comprises with docetaxel or taxol and treating.
In one embodiment, the invention provides a kind for the treatment of, compacting GnRH activator resistance prostate cancer, reduce its incidence of disease, reduce its seriousness, increase its survival rate or suppress the method for GnRH activator resistance prostate cancer.In another embodiment, GnRH activator is Leuprorelin.
In one embodiment, the invention provides a kind for the treatment of, compacting GnRH antagonist (GRHA) resistance prostate cancer, reduce its incidence of disease, reduce its seriousness, increase its survival rate or suppress the method for GnRH antagonist (GRHA) resistance prostate cancer.In another embodiment, GRHA activator is Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2.
In one embodiment, the invention provides a kind for the treatment of, compacting antiandrogen resistance prostate cancer, reduce its incidence of disease, reduce its seriousness, increase its survival rate or suppress the method for antiandrogen resistance prostate cancer.In another embodiment, antiandrogen is the assorted Shandong of Bicalutamide, Flutamide or grace amine.
In one embodiment, the invention provides a kind for the treatment of, compacting vaccine resistance prostate cancer, reduce its incidence of disease, reduce its seriousness, increase its survival rate or suppress the method for vaccine resistance prostate cancer.
In one embodiment, the invention provides a kind for the treatment of, compacting abiraterone resistance prostate cancer, reduce its incidence of disease, reduce its seriousness, increase its survival rate or suppress the method for abiraterone resistance prostate cancer.
In one embodiment, provide and/or use the method for compound provided in this article that the feedback providing about hypothalamic pituitary testicular axis (HPT axle) is provided herein.Feedback refers to that the material regulation and control that produce in a kind of organ or tissue affect the active ability of the another kind of organ or tissue of himself activity.In one embodiment, about the feedback of hypothalamic pituitary testicular axis (HPT axle), cause the reduction of LH level.In one embodiment, about the feedback of hypothalamic pituitary testicular axis (HPT axle), cause the reduction of total serum testosterone levels.In one embodiment, about the feedback of hypothalamic pituitary testicular axis (HPT axle), cause the reduction of free level of serum testosterone.In one embodiment, about the feedback of hypothalamic pituitary testicular axis (HPT axle), cause the reduction of serum, tissue or tumour androgen levels.
Hypothalamus-pituitary-testis (HPT) axle refers to the internal secretion physiological system of the hormonal readiness in regulation and control hypothalamus, hypophysis and testis.LHRH (luteinising hormone-releasing hormo) is discharged by hypothalamus and Stimulation of Pituitary Gland is synthetic and secretion LH and FSH (gonadotropin).Then LH and FSH act on testis to stimulate testosterone and sperm to produce.Then to hypothalamus LHRH, secretion has direct negative feedback and hypophysis LH and FSH generation is had to indirect negative feedback testosterone.Oestrogenic hormone, androgen and haemocyanin (for example, inhibin) also have negative interaction to the secretion of LHRH secretion and LH and FSH.
Hypophysis is a body of gland controlling the testosterone levels in health.When testosterone levels is lower, hypophysis discharges luteinizing hormone (LH).This hormone induction testis produces more polyorchism ketone.Testosterone levels increases in puberty.Testosterone levels is at 20 to 40 years old left and right Shi Gao, and then in elderly men, tails off gradually.Compare with the male sex, women has the testosterone of much smaller amount in their health.But testosterone plays an important role in the male sex and women's whole body.It affects brain, bone and muscle quality, Fat Distribution, vascular system, energy level, germinal tissue and sexual function.Most of testosterone in blood be called as sex hormone binding globulin (SHBG) protein or be called as albuminous another kind of haemocyanin and be combined.Also can clinical assays in conjunction with the testosterone of (or " dissociating ").
In another embodiment, it is the increase due to sex hormone binding globulin (SHBG) that the reduction that is independent of serum luteinizing hormone level reduces total serum testosterone, free level of serum testosterone or free serum testosterone percentage (free T%).In another embodiment, it is the increase due to sex hormone binding globulin (SHBG) that the reduction that is independent of serum luteinizing hormone level reduces free testosterone level.In another embodiment, it is the increase due to sex hormone binding globulin (SHBG) that the reduction that is independent of serum luteinizing hormone level reduces free testosterone percentage (free T%).In another embodiment, it is because the interstitial glands in testis (Leydig cell) produces or the inhibition of Testosterone Secretion that the reduction that is independent of serum luteinizing hormone (LH) level reduces total serum or free level of serum testosterone.In another embodiment, the reduction that is independent of serum luteinizing hormone (LH) level reduces total serum or free level of serum testosterone is the minimizing generating due to adrenal steroid.
In one embodiment, compound and/or the composition that comprises described compound can be for reducing luteinizing hormone (LH) levels as described herein.In another embodiment, compound of the present invention and/or composition can be for reducing endogenous sex hormones.
Hydroxysteroid dehydrogenase (HSD) family member relate in the conversion of circulation steroids.17 β-HSD5 changes into androstenedione testosterone and oestrone is changed into estradiol.In addition, it also relates in prostaglandin is synthetic.In one embodiment, compound of the present invention suppresses HSD, and specifically 17beta-Hydroxysteroid dehydrogenase 5 (17 β-HSD5) suppresses.Described inhibition can be by preventing the synthetic ADT that is applicable to of the outer testosterone of periphery/sexual gland, the synthetic HPT axle that may depart from of the outer testosterone of periphery/sexual gland is controlled and causes total or free serum testosterone not exclusively to reduce or allow testosterone levels in the local cell raising, and any one may be harmful in ADT.
The initial impulse (being called as " rubescent reaction (flare reaction) ") that the androgen-deprivation therapy (ADT) realizing by LHRH agonist therapy (using luteinising hormone-releasing hormo activator (LHRH) or its analog) causes gonadotropin to produce from testis from release and the testosterone of hypophysis is then the minimizing of gonadotropin releasing hormone and the reduction of testosterone levels and estrogen level." the rubescent reaction " that by LHRH agonist therapy, caused has negative effect to the treatment of prostate cancer, and this is because androgen/testosterone levels increases.In addition LHRH therapy be always associated with the diabetes and the risk of cardiovascular diseases that increase (Smith (2008) Current Prostate Reports.6:149-154).
In the work of rubescent effect that overcomes LHRH therapy, LHRH/ antiandrogen methods for the treatment of and lhrh antagonist (Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2) (Suzuki etc., (2008) Int.J.Clin.Oncol.13:401-410 of provide antiandrogen monotherapy (Bicalutamide, Flutamide, chlormadinone), combining; Sharifi, N. etc., (2005) JAMA.294 (2): 238-244).Antiandrogen monotherapy can not reduce the androgen levels in experimenter.It is so effective that the demonstration in the patients with prostate cancer with bone transfer of Bicalutamide antiandrogen monotherapy is not so good as ADT.In addition, the viewed detrimental effect of Bicalutamide therapy comprise breast tenderness and breast increase (gynecomastia and mastodynia) (Suzuki etc., ibid).The other risk of anti androgenic therapy comprises the liver transaminase (ibid such as Sharifi) of increase.
In one embodiment, the invention provides the reduction of LH level and the reduction of total serum testosterone and/or free level of serum testosterone whereby, and do not produce " rubescent " effect, and overcome by using the testosterone of traditional ADT method to reduce the caused detrimental effect being associated with estrogen deficiency simultaneously.Method/the purposes of motif compound provides tissue selectivity estrogen active, described activity the maintaining of bone tissue (the activator effect to bone tissue), the thrombotic potentiality that reduce and/or hot flash are provided and/or to breast tissue than estradiol or the less or neutral effect of diethylstilbestrol
In one embodiment, compound IV shows activator effect and does not show antagonism (embodiment 6 and 7), so compound IV can not cause the increase of gonadotropin and testosterone.
In one embodiment, compound IV shows agonist activity (embodiment 8 to 11), thereby proof is for the strong pharmacological reaction of serum hormone, testosterone and total androgenic minimizing.
In one embodiment, compound IV is on-steroidal selective estrogen receptor α (ER α) activator with nanomole affinity conjugated estrogen hormone acceptor (ER) to ER α and ER β.Although many estrogen ligands and other nuclear hormone receptor cross reaction, the effect of compound IV has specificity to ER α and ER β.Compare with estradiol, compound IV has 16 times of selectivity aspect the relative trans-activation effect for ER α and ER β, and has the effect of little approximately 1400 times stimulating aspect the beta mediated ability of transcribing of ER.
In one embodiment, the method for use provided in this article compound provided in this article and/or composition is effective in and reduces or eliminates by using the ADT of traditional form to reduce the caused bone absorption effect of LH.In one embodiment, provide herein and/or use the method for composition provided in this article to be effective in the caused bone absorption effect of ADT reduction testosterone levels reducing or eliminating by using traditional form.In one embodiment, the method for use provided in this article composition provided in this article is effective in to reduce or eliminate by LH level and reduces the bone absorption effect that the minimizing of the testosterone cause causes.In one embodiment, the prevention of the method for use provided in this article compound provided in this article and/or composition reduces with the ADT with traditional form the bone absorption effect that LH Horizontal correlation joins.In one embodiment, the prevention of the method for use provided in this article compound provided in this article and/or composition reduces with the ADT with traditional form the bone-loss that endogenous LH, testosterone and/or estradiol are associated.In one embodiment, the method for use provided in this article compound provided in this article and/or composition increases bone mass density (BMD), and provides LH level to reduce simultaneously.In one embodiment, the method for use provided in this article compound provided in this article and/or composition increases bone volume percentage, and provides endogenous LH, testosterone and/or estradiol level to reduce simultaneously.
In some embodiments, the invention provides a kind of method of avoiding and/or reduce thromboembolism by using compound of the present invention or its isomer, medicinal product, polymorph, hydrate or its any combination.
In one embodiment, method provided in this article, that use compound provided in this article and/or composition is effective in breast tissue.In one embodiment, provided in this article, method that use compound provided in this article and/or composition provides the reduction of LH level, and prevention simultaneously reduces with the LH level realizing by traditional ADT the gynecomastia being associated.
In one embodiment, the open specific toxicity research of embodiment 13, wherein shows that with the in vitro study that human blood platelets carries out compound IV has the procoagulant activity more much lower than DES.Therefore, compound IV (a kind of ER selective agonist) should be in the situation that the prostate cancer benefit that the thrombotic episodes risk less than DES sent DES, and the benefit of sending LHRH activator or antagonist, and do not cause bone-loss, hot flash or unfavorable lipid feature.
Show that DES prevention suffers from the bone absorption effect in the patient of prostate cancer separately or with diethyl diethylstilbestrol (DES) therapy of other ADT combination.Although the therapy as prostate cancer has been promoted in the use of DES, DES is considered to mediated and do not thought and work by estrogen receptor by DES metabolite to the effect of Angiogenesis and malignant tumour.In addition, the dosage level that is used for the treatment of the DES that purposes uses presents many adverse side effects, comprise that vascular disease, cardiovascular morbidity, thrombotic toxicity, gynecomastia, erectile dysfunction and sexual desire reduce (Scherr and Pitts, ibid and Presti, J.C.Jr. (1996) JAMA.275 (15): 1153-6).
In one embodiment, the present invention combines the negative side-effects that overcomes LHRH activator or antagonist therapy individually or with antiandrogen or DES.In another embodiment, method of the present invention provides androgen-deprivation therapy, and without unfavorable estrogen deprivation side effect (as the symptom of unfavorable bone photo pass) and without unfavorable oestrogenic hormone stimulation side effect (as gynecomastia).In another embodiment, method of the present invention provides the reduction of LH level and reduction total whereby and/or free level of serum testosterone, and do not produce " rubescent " effect, overcome the detrimental effect relevant to the estrogen deficiency being caused by LH minimizing simultaneously and overcome the detrimental effect being associated with the viewed overall estrogen agonist increase of DES therapy.Method/the purposes of motif compound provides tissue selectivity estrogen active, thereby the thrombotic potentiality and the neutralism to breast tissue that maintain (the activator effect to bone tissue), reduce of bone tissue are provided.
Traditional selective estrogen receptor modulators (SERM) in hypothalamus level causes the increase of Gonadotropin Level in the male sex or the increase of LH level as the estrogenic antagonist of Tamoxifen, Toremifene and Raloxifene, and the increase (Tsouri etc. that cause potentially whereby testosterone serum levels, 2008, Fertility and Sterility doi:10.1016).By contrast, method of the present invention provides the minimizing of the LH in male subject, and described method comprises uses formula IA, I to XII compound.
other embodiment of formula I compound:
In an embodiment of method of the present invention, the Y of formula I compound is C (O).In another embodiment, Y is CH 2.In another embodiment, the R of formula I or IA compound 1and R 2o-Alk-NR independently 5r 6or O-Alk-heterocycle.In another embodiment, described O-Alk-heterocycle, O-Alk-NR as described above 5r 6,-Alk-heterocycle and Alk-NR 5r 6alk be that the straight chained alkyl of 1 to 7 carbon is, the cyclic alkyl of the branched alkyl of 1 to 7 carbon or 3 to 8 carbon.In another embodiment, alkyl is ethylidene (CH 2cH 2-).In another embodiment, Alk is methylene (CH 2-).In another embodiment, Alk is propylidene (CH 2cH 2cH 2-).In another embodiment, Alk is 2-methyl propylidene (CH 2cH (CH 3) CH 2-).
In an embodiment of method of the present invention, the R of formula I or IA compound 1in contraposition.In an embodiment of method of the present invention, the R of formula I or IA compound 1and R 2different.In another embodiment of method of the present invention, the R of formula I or IA compound 1and R 2identical.In another embodiment of method of the present invention, the R of formula I or IA compound 1be in another embodiment of described method, the R of formula I or IA compound 1it is hydroxyl.In another embodiment of described method, the R of formula I or IA compound 1it is alkoxyl.In another embodiment of described method, R 1and R 2hydrogen, halogen, hydroxyl, alkoxyl, cyano group, nitro, CF independently 3, N (R) 2, sulfonamide, SO 2r, alkyl, alkylhalide group, aryl, O-Alk-NR 5r 6or O-Alk-heterocycle, wherein heterocycle be 3 yuan to heterocycle 7 yuan of replacements or unsubstituted, be optionally aromatic.In another embodiment of described method, the R of formula I or IA compound 1and R 2halogen, hydroxyl, alkoxyl, cyano group, nitro, CF independently 3, N (R) 2, sulfonamide, SO 2r, alkyl, alkylhalide group, aryl, O-Alk-NR 5r 6or O-Alk-heterocycle, wherein heterocycle be 3 yuan to heterocycle 7 yuan of replacements or unsubstituted, be optionally aromatic.In another embodiment of described method, the R of formula I or IA compound 2it is halogen.In another embodiment of described method, the R of formula I or IA compound 2f.In another embodiment of described method, the R of formula I compound 2cl.In another embodiment of described method, the R of formula I or IA compound 2br.In another embodiment of described method, the R of formula I or IA compound 2i.In another embodiment of described method, the R of formula I or IA compound 2it is hydroxyl.In another embodiment of described method, R 1and/or R 2cF 3.In another embodiment, R 1and/or R 2cH 3.In another embodiment, R 1and/or R 2it is halogen.In another embodiment, R 1and/or R 2f.In another embodiment, R 1and/or R 2cl.In another embodiment, R 1and/or R 2br.In another embodiment, R 1and/or R 2i.In another embodiment, the R of formula I compound 2in contraposition.
In an embodiment of method of the present invention, the R of formula I or IA compound 3and R 4identical.In another embodiment of method of the present invention, the R of formula I or IA compound 3and R 4different.In another embodiment of described method, the j of formula I or IA compound and k are 1 independently.In another embodiment of described method, the R of formula I or IA compound 3and R 4halogen, alkylhalide group, hydroxyl or alkyl independently.In another embodiment of described method, the R of formula I or IA compound 3and R 4f independently.In another embodiment of described method, the R of formula I or IA compound 3and R 4br independently.In another embodiment of described method, the R of formula I or IA compound 3and R 4cl independently.In another embodiment, R 4in contraposition.In another embodiment, R 3in ortho position.In another embodiment, R 3in a position.In another embodiment, R 3and/or R 4cF 3.In another embodiment, R 3and/or R 4cH 3.
In an embodiment of method of the present invention, the R of formula I or IA compound 5and R 6form 3 yuan to 7 rings together with nitrogen-atoms.In another embodiment, ring is saturated or unsaturated ring.In another embodiment, ring is that replace or unsubstituted ring.In another embodiment of method of the present invention, the R of formula I or IA compound 5and R 6form piperidine ring together with nitrogen.In another embodiment of described method, the R of formula I or IA compound 5and R 6form pyrazine ring together with nitrogen.In another embodiment of described method, the R of formula I or IA compound 5and R 6form piperazine ring together with nitrogen.In another embodiment of described method, the R of formula I or IA compound 5and R 6form morpholine ring together with nitrogen.In another embodiment of described method, the R of formula I or IA compound 5and R 6form pyrrole ring together with nitrogen.In another embodiment of described method, the R of formula I or IA compound 5and R 6form pyrrolidines.In another embodiment of described method, the R of formula I or IA compound 5and R 6form pyridine ring together with nitrogen.In another embodiment, ring is replaced by halogen, alkyl, alkoxyl, alkylidene, hydroxyl, cyano group, nitro, amino, acid amides, COOH or aldehyde.
In another embodiment of method of the present invention, the R of formula I or IA compound 1r with formula I or IA compound 2o-Alk-heterocycle or OCH independently 2cH 2-heterocycle.In another embodiment, term " heterocycle " group refers in one embodiment and except carbon atom, comprises sulphur, oxygen, nitrogen or its any combination as the ring structure of a part for ring.In another embodiment, heterocycle be 3 yuan to 12 rings.In another embodiment, heterocycle is 6 rings.In another embodiment, heterocycle be 5 yuan to 7 rings.In another embodiment, heterocycle be 4 yuan to 8 rings.In another embodiment, heterocyclic group can be unsubstituted or be replaced below: halogen, alkylhalide group, hydroxyl, alkoxyl, carbonyl, amide groups, alkylamidoalkyl, dialkyl amide base, cyano group, nitro, CO 2h, amino, alkyl amino, dialkyl amido, carboxyl, sulfo-and/or alkylthio.In another embodiment, heterocycle can with another saturated or unsaturated cycloalkyl or 3 yuan to 8 yuan heterocyclic fused.In another embodiment, heterocycle is saturated ring.In another embodiment, heterocycle is undersaturated ring.In another embodiment, heterocycle is piperidines.In another embodiment, heterocycle is pyridine.In another embodiment, heterocycle is piperidines, pyridine, furans, thiophene, pyrroles, pyrrolidines, pyrazine, piperazine or pyrimidine.
Term " cycloalkyl " refers to the monocycle of the non-aromatic that comprises carbon atom and hydrogen atom or encircles more.Cycloalkyl can have one or more carbon-to-carbon double bonds in ring, as long as the existence of carbon-to-carbon double bond does not make this ring have aromaticity.The example of cycloalkyl includes but not limited to that (C3-C7) cycloalkyl is as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and suberyl, with saturated cyclic terpene and dicyclo terpene, and (C3-C7) cycloalkenyl group as cyclopropanyl, cyclobutane base, cyclopentenyl, cyclohexenyl group and cycloheptenyl, and undersaturated cyclic terpene and dicyclo terpene.Cycloalkyl can be unsubstituted or be replaced by one or two substituting group.Preferably, cycloalkyl is monocycle or dicyclo.
Term " alkyl " refers to saturated aliphatic hydrocarbon in one embodiment, comprises straight chain, side chain and cyclic alkyl.In one embodiment, alkyl has 1 to 12 carbon.In another embodiment, alkyl has 1 to 7 carbon.In another embodiment, alkyl has 1 to 6 carbon.In another embodiment, alkyl has 1 to 4 carbon.In another embodiment, cyclic alkyl has 3 to 8 carbon.In another embodiment, cyclic alkyl has 3 to 12 carbon.In another embodiment, the alkyl that branched alkyl is replaced by the alkyl side chain of 1 to 5 carbon.In another embodiment, the alkyl that branched alkyl is replaced by the alkylhalide group side chain of 1 to 5 carbon.Alkyl can be unsubstituted or be replaced below: halogen, alkylhalide group, hydroxyl, alkoxyl, carbonyl, amide groups, alkylamidoalkyl, dialkyl amide base, nitro, amino, alkyl amino, dialkyl amido, carboxyl, sulfo-and/or alkylthio.
" thiazolinyl " refers to unsaturated hydrocarbon in another embodiment, comprises straight chain, side chain and the cyclic group with one or more pairs of keys.Thiazolinyl can have two keys, two two keys, three two keys etc.In another embodiment, thiazolinyl has 2 to 12 carbon.In another embodiment, thiazolinyl has 2 to 6 carbon.In another embodiment, thiazolinyl has 2 to 4 carbon.The example of thiazolinyl is vinyl, acrylic, cyclobutenyl, cyclohexenyl group etc.Thiazolinyl can be unsubstituted or be replaced below: halogen, hydroxyl, alkoxyl, carbonyl, amide groups, alkylamidoalkyl, dialkyl amide base, nitro, amino, alkyl amino, dialkyl amido, carboxyl, sulfo-and/or alkylthio.
" aryl " refers to the aromatic group with at least one carbon-ring aromatic group or heterocyclic aromatic group, and it can be unsubstituted or is selected from following one or more groups and replace: halogen, alkylhalide group, hydroxyl, alkoxyl, carbonyl, acylamino-, alkyl amido, dialkyl group acylamino-, nitro, amino, alkyl amino, dialkyl amido, carboxyl or sulfo-or alkylthio.The limiting examples of aromatic ring is phenyl, naphthyl, pyranose, pyrrole radicals, pyrazinyl, pyrimidine radicals, pyrazolyl, pyridine radicals, furyl, thio-phenyl, thiazolyl, imidazole radicals, isoxazolyl etc.In one embodiment, aryl be 4 yuan to 8 rings.In another embodiment, aryl be one or more 4 yuan to 12 rings.In another embodiment, aryl is 6 rings.In another embodiment, aryl is 5 rings.In another embodiment, aryl is 2 yuan to 4 yuan fused rings system rings.
" aldehyde " base refers to the alkyl or alkenyl being replaced by formoxyl in one embodiment, and wherein alkyl or alkenyl is as hereinbefore defined.In another embodiment, the aryl that aldehyde radical is replaced by formoxyl or phenyl, wherein aryl is as hereinbefore defined.The example of aldehyde is: formoxyl, acetal, propionic aldehyde, butyraldehyde, valeral, benzaldehyde.In another embodiment, aldehyde radical is formoxyl.
" alkylhalide group " refers to alkyl as defined above in another embodiment, and it is for example replaced by F, Cl, Br or I by one or more halogen atoms.
" hydroxyl " refers to OH group in another embodiment.One skilled in the art will understand that the R in compound of the present invention 1, R 2or R 3while being OR, R is not OH.
In one embodiment, term " halogen (halogen) " or " halogen (halo) " refer to halogen, as F, Cl, Br or I.
In another embodiment, phrase " phenol " refers to alcohol (OH) derivative of benzene.
In some embodiments, mention that shielded hydroxyl comprises the substituting group being incorporated to the oxygen part bonding of phenyl ring, wherein substituting group can easily be removed.In some embodiments, phenol blocking group can comprise: methyl ether (methoxyl group), alkyl ether (alkoxyl), benzylic ether (Bn), methoxy (MOM) ether, benzoyl oxygen ylmethyl (BOM) ether, benzyl, benzyloxycarbonyl group, methoxy ethoxy methyl (MEM) ether, 2-(trimethyl silyl) ethoxyl methyl (SEM) ether, methylthiomethyl (MTM) ether, thiophenyl methyl (PTM) ether, azido methyl ether, cyano methyl ether, 2,2-bis-is chloro-1,1-difluoro ethyl ether, 2-chloroethyl ether, 2-bromoethyl ether, THP trtrahydropyranyl (THP) ether, 1-ethoxyethyl group (EE) ether, phenacyl ether, 4-bromobenzene formyl methyl ether, cyclopropyl methyl ether, allyl ether, propargyl ether, isopropyl ether, cyclohexyl ether, tertbutyl ether, 2,6-dimethyl benzyl ether, 4-methoxy-benzyl ether, adjacent nitrobenzyl ether, 2,6-dichloro benzyl ether, 3,4-dichloro benzyl ether, 4-(dimethylamino) carbonyl benzylic ether, 4-methylsulfinyl benzylic ether, 4-anthryl methyl ether, 4-picolyl (picolyl) ether, seven fluoro-p-methylphenyls, tetrafluoro-4-pyridyl ethers, trimethyl silyl (TMS) ether, t-butyldimethylsilyl (TBDMS) ether, t-butyldiphenylsilyl (TBDPS) ether, triisopropyl silicyl (TIPS) ether, formic acid aryl ester, acetic acid aryl ester, levulinic acid aryl ester, neopentanoic acid aryl ester, benzoic acid aryl ester, 9-fluorenes formic acid aryl ester, aryl carbonates methyl ester, carbonic acid 1-adamantane esters, carbonic acid tertiary butyl ester, carbonic acid 4-methylsulfinyl benzyl ester, carbonic acid 2,4-dimethyl-penten-3-base ester, aryl carbonates 2,2,2-trichloro ethyl ester, aryl carbonates benzyl ester, aryl carbamate, dimethyl oxygen phosphino-ester (Dmp-OAr), dimethyl phosphino-sulfinyl ester (Mpt-OAr), diphenylphosphino sulfinyl ester (Dpt-OAr), methanesulfonic acid aryl ester, toluenesulfonic acid aryl ester or 2-formoxyl benzene sulfonic acid aryl ester.
In one embodiment, method of the present invention is utilized N, two (4-the hydroxy phenyl)-4-propyl benzamides (II) of N-or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination.In another embodiment, method of the present invention is utilized 4,4'-(2,3-dimethyl-benzyl azane, two bases) biphenol (III) or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination.In another embodiment, method of the present invention is utilized the fluoro-N-of 3-(4-fluorophenyl)-4-hydroxy-n-(4-hydroxy phenyl) benzamide (IV) or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination.In another embodiment, method of the present invention is utilized N, two (the 4-hydroxy phenyls)-2 of N-, 3-dimethyl benzamide (V) or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination.In another embodiment, method of the present invention is utilized N, two (4-the hydroxy phenyl)-2-naphthalene amino acids (VI) of N-or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination.In another embodiment, method of the present invention is utilized the fluoro-4-hydroxy-n of 3-, two (4-the hydroxy phenyl)-benzamides (VII) of N-or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination.In another embodiment, method of the present invention is utilized 4-((4-fluorophenyl) (4-hydroxybenzyl) amino) phenol (VIII) or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination.In another embodiment, method of the present invention is utilized the fluoro-N-of 4-(4-hydroxyl-phenyl)-N-[4-(2-piperidin-1-yl-ethyoxyl)-phenyl]-2-trifluoromethyl-benzamide (IX) or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination.In another embodiment, method of the present invention is utilized hydrochloride (the HCl salt of IX) or the fluoro-N-of 4-(4-hydroxyl-phenyl)-N-[4-(2-piperidin-1-yl-ethyoxyl)-phenyl of IX]-2-trifluoromethyl-benzamide hydrochloride salt (X) or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination.In another embodiment, method of the present invention is utilized the fluoro-4-hydroxy-n of 3--(4-hydroxy phenyl)-N-phenylbenzamaide (XI) or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination.In another embodiment, method of the present invention is utilized the fluoro-N of 3-, N-pair-(4-hydroxyl-phenyl)-2-methyl-benzamide (XII) or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination.
In one embodiment, method of the present invention is utilized " pharmaceutically acceptable salt " of described compound, and it can be by producing compound of the present invention and acid or alkali reaction.
The applicable pharmaceutically acceptable salt of the amine of the compound of method of the present invention can be prepared by inorganic acid or organic acid.In one embodiment, the example of the mineral salt of amine is disulfate, borate, bromide, chloride, Hemisulphate, hydrobromate, hydrochloride, 2-isethionate (hydroxyethanesulfonic acid salt), iodate, iodide, different thiosulfate, nitrate, persulfate, phosphate, sulphate, sulfamate, sulfanilate, sulfonic acid (arylsulphonate that the alkylsulfonate that alkylsulfonate, arylsulphonate, halogen replace, halogen replace), sulfonate and rhodanate
In one embodiment, the example of the organic salt of amine can be selected from aliphatic, cyclic aliphatic, aromatic series, araliphatic, heterocycle, the organic acid of carboxylic acid and sulphonic acids, the example is acetate, arginine, aspartate, ascorbate, adipate, anthranilate, algenates, alkanecarboxylic acid salt, the alkanecarboxylic acid salt replacing, alginates, benzene sulfonate, benzoate, disulfate, butyrate, bicarbonate, biatrate, carboxylate, citrate, camphorate, camsilate, cyclohexyl-n-sulfonate, cyclopentane propionate, Ca-EDTA, camsilate (camsylates), carbonate, Clavulanate (clavulanate), cinnamate, dicarboxylate, digluconate, dodecane sulfonate (dodecylsulfonates), dihydrochloride (dihydrochlorides), caprate, enanthate (enanthuate), esilate, edetate (edetates), ethanedisulphonate (edisylates), estolate (estolates), esilate (esylates), fumarate, formates, fluoride, galacturonic hydrochlorate (galacturonate), gluconate, glutamate, glycollate (glycolates), gluconate (glucorates), glucoheptose salt (glucoheptanoate), glycerophosphate, gluceptate (gluceptates), to hydroxyl acetylamino phenyl-arsonate (glycollylarsanilates), glutarate, glutamate, enanthate, caproate, hydroxymaleic acid salt (hydroxymaleates), hydroxycarboxylic acid, hexyl resorcin salt (hexylresorcinates), hydroxy benzoate, Hydroxynaphthoate, hydrofluoride (hydrofluorates), lactate, Lactobionate (lactobionates), laruate, malate, maleate, di-2-ethylhexylphosphine oxide (β-chomene formates), malonate, mandelate, mesylate, methane sulfonates, methyl bromide (methylbromides), methyl nitrate (methylnitrates), metilsulfate, maleic acid list potassium (monopotassium maleate), mucate (mucates), monocarboxylate, nitrate, naphthalene sulfonate, 2-naphthalene sulfonate, nicotinate, naphthalene sulfonate (napsylates), N-METHYL-ALPHA-L-GLUCOSAMINE, oxalate, caprylate, oleate, pamoate (pamoate), phenylacetate (phenylacetate), picrate (picrate), phenylbenzoate (phenylbenzoate), Pivalate, propionate, phthalate, pectate (pectinates), phenylpropionic acid salt (phenylpropionate), palmitate, pantothenate, Polygalacturonate (polygalacturates), acetonate, quinate, salicylate, succinate, stearate, sulfanilate, basic acetate (subacetates), tartrate, cariamyl (theophyllineacetates), p-toluene fulfonate (toluene fulfonate), trifluoroacetate, terephthalate (terephthalate), tannate (tannate), teoclate (teoclates), three halogen acetic acid salt (trihaloacetates), triethiodide, tricarboxylate, undecylate (undecanoates) and valerate.
In one embodiment, the example of the mineral salt of carboxylic acid or phenol can be selected from ammonium, alkali metal, comprises lithium, sodium, potassium, caesium; Alkaline earth metal, comprises calcium, magnesium, aluminium; Zinc, barium, choline, quaternary ammonium.
In another embodiment, the example of the organic salt of carboxylic acid or phenol can be selected from arginine, organic amine, comprise aliphatic organic amine, alicyclic organic amine, aromatic series organic amine, tardocillin (benzathines), tert-butylamine, phenylethylbenzylamine (benethamines) (N-benzyl-1-phenylethylamine), dicyclohexyl amine, dimethylamine, diethanol amine, monoethanolamine, ethylenediamine, Hai Baming, imidazoles, lysine, methylamine, meglumine (meglamines), N-methyl D-aminoglucose, N, N'-dibenzyl-ethylenediamin, vitamin PP, organic amine, ornithine, pyridine, picoline (picolies), piperazine, procain (procain), trihydroxymethylaminomethane, triethylamine, triethanolamine, trimethylamine, tromethamine (tromethamines) and urea.
In one embodiment, can form salt by conventional method, as by make the suitable acid of the free alkali of product or free acid form and one or more equivalents or alkali as described in the insoluble solvent of salt or medium or react in solvent (as water), remove solvent in a vacuum or by freeze drying, or by making the ion exchange of existing salt become another kind of ion or applicable ion exchange resin.
In one embodiment, method of the present invention is utilized the pharmaceutically acceptable salt of compound of the present invention.In one embodiment, method of the present invention is utilized the pharmaceutically acceptable salt of formula IA, I to XII compound.In one embodiment, method of the present invention is utilized the salt of the amine of formula IA of the present invention, I to XII compound.In one embodiment, method of the present invention is utilized the salt of the phenol of formula IA of the present invention, I to XII compound.
In one embodiment, method of the present invention is utilized free alkali, free acid, uncharged or non-compound compound and/or its isomer, medicinal product, hydrate, polymorph or its combination of formula IA, I to XII.
In some embodiments of the present invention, compound of the present invention comprises three phenyl that combine by amido link.In one embodiment, the charged structure of compound right and wrong of the present invention.In another embodiment, compound of the present invention is free alkali structure.In another embodiment, compound of the present invention is free acid structure.In another embodiment, compound of the present invention is non-composite construction.In another embodiment, compound of the present invention is non-ionic structure.In another embodiment, compound of the present invention is pharmaceutically acceptable salt.In another embodiment, compounds more of the present invention comprise hydrochloric acid (HCl) salt.
In one embodiment, method of the present invention is utilized the isomer of formula IA, I to XII compound.In one embodiment, method of the present invention is utilized the medicinal product of formula IA, I to XII compound.In one embodiment, method of the present invention is utilized the hydrate of formula IA, I to XII compound.In one embodiment, method of the present invention is utilized the polymorph of formula IA, I to XII compound.In one embodiment, method of the present invention is utilized the metabolite of formula IA, I to XII compound.In another embodiment, method utilization of the present invention comprises the composition of formula IA, I to XII compound as described herein, or in another embodiment, the composition of the combination of the isomer that method utilization of the present invention comprises formula IA, I to XII compound, metabolite, medicinal product, hydrate, polymorph.
In one embodiment, term " isomer " includes but not limited to optical isomer and analog, constitutional isomer and analog, rotamer and analog etc.
In one embodiment, term " isomer " refers to the optical isomer of containing compound.In one embodiment, term " isomer " refers to the stereoisomer of containing compound.Compound of the present invention has amido link, and described amido link can be cis or trans-isomerism.Should be understood that the present invention contains any optical activity or stereoisomeric forms in any ratio or its mixture, and these forms should be considered within the scope of the invention for the purposes of any application.
In another embodiment, the present invention further comprises the hydrate of compound.In one embodiment, term " hydrate " refers to as known in the art semihydrate, monohydrate, dihydrate, trihydrate or other.
synthetic method
Can (for example) come easily preparation formula I or IA compound by making the diphenylamine of replacement react to obtain benzamide with benzoic acid or benzoyl halogen in the situation that there is alkali.In one embodiment, alkali is pyridine.In another embodiment, benzoyl halogen is chlorobenzoyl chloride.In another embodiment, in the course of reaction of hydroxyl substituent between diphenylamine and benzoic acid or benzoyl halogen, be shielded.In another embodiment, optionally in the end remove the blocking group of hydroxyl in a step.Also, referring to U.S.'s publication No. 2009/00624231 and United States Patent (USP) 8,158,828, described document by reference integral body is incorporated to.
For example, formula IA compound:
R wherein 1, R 2, R 3and R 4, j and k be as described above; Can prepare by the following method, described method comprises to be made
With
Reaction is to produce:
and
Make diphenylamine (3) with
In the situation that there is alkali, reaction is to produce
If R wherein 1, R 2, R 3and R 4oH, O-Alk-R independently 5r 6or O-Alk-heterocycle, so R 1', R 2', R 3', R 4' be shielded hydroxyl, wherein blocking group removed to obtain free hydroxyl group or optionally follow and Cl-Alk-heterocycle or Cl-Alk-NR 5r 6reaction is with production IA compound:
Wherein, if R 1, R 2, R 3and R 4be different from independently OH, O-Alk-NR 5r 6or O-Alk-heterocycle, so R 1', R 2', R 3' and R 4' be respectively R 1, R 2, R 3and R 4.
As another example, a kind of method for the preparation of formula IA compound:
R wherein 1, R 2, R 3and R 4be as described above, described method comprises to be made
With
In the situation that there is alkali, reaction is to produce
If R wherein 1, R 2, R 3and R 4oH, O-Alk-R independently 5r 6or O-Alk-heterocycle, so R 1', R 2', R 3', R 4' be shielded hydroxyl, wherein blocking group removed to obtain free hydroxyl group or optionally follow and Cl-Alk-heterocycle or Cl-Alk-NR 5r 6reaction is with production IA compound:
Wherein, if R 1, R 2, R 3and R 4be different from independently OH, O-Alk-NR 5r 6or O-Alk-heterocycle, so R 1', R 2', R 3' and R 4' be respectively R 1, R 2, R 3and R 4.
In an example, according to embodiment 1 and Fig. 5, prepare Compound I I.
In another example, according to embodiment 1 and Fig. 5, prepare compound III.
In other example, formula IV compound (compound IV):
Can be by with the preparation of getting off: make
With
In the situation that there is alkali, reaction is to produce
Then make blocking group deprotection to produce compound IV:
Wherein P and P ' are identical or different blocking groups.In an example, according to embodiment 2 and Fig. 6, prepare compound IV.
In another example, according to embodiment 1 and Fig. 5, prepare compound V.
In other example, according to embodiment 3 and Fig. 7, prepare compound VI.
In another example, according to embodiment 1 and Fig. 5, prepare compound VI I.
In another example, according to embodiment 4 and Fig. 5, prepare compound VI II.
In another example, according to embodiment 5 and Fig. 8, prepare Compound I X.
In another example, according to embodiment 5 and Fig. 8, prepare compounds X hydrochloride.
In another example, according to embodiment 1 and Fig. 5, prepare compounds X I.
In another example, according to embodiment 1 and Fig. 5, prepare compounds X II.
Applicable hydroxy-protective group comprises, for example, and methyl ether (methoxyl group), benzylic ether (benzyloxy), methoxy (MOM) ether, benzoyl oxygen ylmethyl (BOM) ether, benzyl, benzyloxycarbonyl group, methoxy ethoxy methyl (MEM) ether, 2-(trimethyl silyl) ethoxyl methyl (SEM) ether, methylthiomethyl (MTM) ether, thiophenyl methyl (PTM) ether, azido methyl ether, cyano methyl ether, 2,2-bis-is chloro-1,1-difluoro ethyl ether, 2-chloroethyl ether, 2-bromoethyl ether, THP trtrahydropyranyl (THP) ether, 1-ethoxyethyl group (EE) ether, phenacyl ether, 4-bromobenzene formyl methyl ether, cyclopropyl methyl ether, allyl ether, propargyl ether, isopropyl ether, cyclohexyl ether, tertbutyl ether, benzylic ether, 2,6-dimethyl benzyl ether, 4-methoxy-benzyl ether, adjacent nitrobenzyl ether, 2,6-dichloro benzyl ether, 3,4-dichloro benzyl ether, 4-(dimethylamino) carbonyl benzylic ether, 4-methylsulfinyl benzylic ether, 4-anthryl methyl ether, 4-picolyl ether, seven fluoro-p-methylphenyls, tetrafluoro-4-pyridyl ethers, trimethyl silyl (TMS) ether, t-butyldimethylsilyl (TBDMS) ether, t-butyldiphenylsilyl (TBDPS) ether, triisopropyl silicyl (TIPS) ether, formic acid aryl ester, acetic acid aryl ester, levulinic acid aryl ester, neopentanoic acid aryl ester, benzoic acid aryl ester, 9-fluorenes formic acid aryl ester, aryl carbonate ester methyl ester, carbonic acid 1-adamantane esters, carbonic acid tertiary butyl ester, carbonic acid 4-methylsulfinyl benzyl ester, carbonic acid 2,4-dimethyl-penten-3-base ester, aryl carbonates 2,2,2-tri-chloro-ethyl esters, aryl carbonates benzyl ester, aryl carbamate, dimethyl oxygen phosphino-ester (Dmp-OAr), dimethyl phosphino-sulfinyl ester (Mpt-OAr), diphenylphosphino sulfinyl ester (Dpt-OAr), methanesulfonic acid aryl ester, toluenesulfonic acid aryl ester or 2-formoxyl benzene sulfonic acid aryl ester.
Method of the present invention comprises the purposes of formula IA or I to XII compound, wherein for the preparation of the method for compound of the present invention, comprises diphenylamine is reacted in the situation that there is alkali with chlorobenzoyl chloride.Applicable alkali comprises, for example, and pyridine, triethylamine, K 2cO 3, Cs 2cO 3, Na 2cO 3, methylamine, imidazoles, benzimidazole, histidine, tri-n-butylamine or its any combination.In one embodiment, alkali is pyridine.
Method of the present invention comprises the purposes of formula IA or I to XII compound, wherein for the preparation of the method for compound of the present invention, comprises the deprotection of shielded hydroxyl.In another embodiment, deprotection condition depends on blocking group.In some embodiments, deprotection steps is included in hydrogenation in the situation that has Pd/C.In another embodiment, deprotection comprises and BBr 3reaction.In another embodiment, deprotection steps comprises and acid reaction.
In other example, according to Fig. 5 to 8 and embodiment 1 to 5 preparation formula IA or I to XII compound.
pharmaceutical composition
In some embodiments, the invention provides using method, it comprises uses the composition that comprises described compound.As used herein, " Pharmaceutical composition " means the active component of " treatment effective dose ", and compound of the present invention is together with pharmaceutically acceptable carrier or thinner." treatment effective dose " refers to the amount that therapeutic action is provided for given symptom and application program as used herein.
As used herein, term administering " be to instigate experimenter to contact with Compound Phase of the present invention.As used herein, use in vitro (for example, in live organism (people's) cell or tissue) in (in test tube) or body and complete.In one embodiment, the present invention is contained compound administration of the present invention to male subject.
In other embodiments, the invention provides the medicinal product of compound described herein.In other embodiments, term " medicinal product " refers to the composition that is suitable for pharmaceutical usage (Pharmaceutical composition), for example, and as described herein.
Compound of the present invention can be used individually or as the active component of preparation.Therefore, the present invention also comprises the Pharmaceutical composition of formula I compound, and described composition contains (for example) one or more pharmaceutically acceptable carriers.
Can obtain many descriptions for the preparation of being suitable for using the canonical reference document according to the program of the different preparations of compound of the present invention.The example of potential preparation and prepared product is included in (for example) with in Publication about Document: Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current version); Pharmaceutical Dosage Forms:Tablets (Lieberman, Lachman and Schwartz edit) current version, by Marcel Dekker, Inc. publish, and Remington's Pharmaceutical Sciences (Arthur Osol edits), 1553-1593 (current version).
Method of application and formulation and for given treatment, to apply be that the therapeutic dose with compounds effective or composition that needs is closely related.
Applicable formulation includes but not limited to, in oral, per rectum, hypogloeeis, mucous membrane, nose, eye, subcutaneous, muscle, intravenous, in skin, spinal cord, sheath, in joint, in artery, under arachnoid, in (sub-arachinoid), bronchi, lymph and uterus, use and for other formulation of systemic delivery active component.It is preferred being suitable for Orally administered preparation.
In order to prepare described pharmaceutical dosage form, can active component be mixed with pharmaceutical carrier according to the medical mixed technology of routine.Carrier can be taked diversified form, and this depends on the form of using required prepared product.
In preparation, be in the composition of peroral dosage form, can adopt any conventional medicinal medium.Therefore,, for liquid oral prepared product, for example, as supensoid agent, elixir and solution, applicable carrier and additive comprise water, glycol, oil, alcohol, flavor enhancement, preservative, colouring agent etc.For Peroral solid dosage form, prepare thing, for example, as powder, capsule and tablet, applicable carrier and additive comprise starch, sugar, thinner, granulating agent, lubricant, adhesive, disintegrant etc.Because it uses easiness, Tablet and Capsula represents best oral dosage unit form.If need, can carry out sweet tablet or enteric coating dressing to tablet by standard technique.
For parenteral formulation, carrier will generally include sterile water, but can comprise other composition, for example, help dissolve or for corrosion-resistant composition.Injectable solution can also be prepared, suitable stabilizing agent can be adopted in this case.
In some applications, maybe advantageously use the activating agent that is " carrier " form, as by activating agent being encapsulated in liposome or other encapsulant medium, or for example, activating agent is fixed in applicable biomolecule by covalent bonding, chelation or association coordination by (), described biomolecule is as being selected from those of protein, lipoprotein, glycoprotein and polysaccharide.
Methods for the treatment of of the present invention is used and is suitable for Orally administered preparation, and described preparation can discrete unit present, and as capsule, cachet, tablet or lozenge, it contains the active component that is powder for example or particle form of scheduled volume separately.Optionally, can adopt the supensoid agent in aqueous solution or non-aqueous liquid, as syrup, elixir, emulsion or potus.
Optionally together with one or more auxiliary elements, by compacting or molded or wet granulation, make tablet.Can as powder or particle, prepare compressed tablets by compression is free-flowing form in applicable machine reactive compound, described reactive compound optionally for example, mixes with () adhesive, disintegrant, lubricant, inert diluent, surfactant or releasing agent (discharging agent).Can be by the molded molded tablet of making the mixture that comprises powdered activated compound and applicable carrier in applicable machine.
Can for example, by reactive compound being added in concentrated sugar (sucrose) aqueous solution, make syrup, can also in the described aqueous solution, add any or multiple auxiliary element.Described one or more auxiliary elements can comprise flavor enhancement, applicable preservative, the reagent that postpones the reagent of sugared crystallization and increase the solvability of any other composition, as polyalcohol, and for example glycerine or sorbierite.
Be suitable for preparation that stomach and intestine use outward and can comprise the sterile aqueous prepared product of reactive compound, described prepared product preferably oozes (for example, normal saline solution) with blood of recipient etc.Described preparation can comprise suspending agent and thickener and liposome or other microparticle system, and described system is designed to for by targeting compounds blood constitutent or one or more organ.Preparation can present with the form of unit dose or multiple dosage.
Stomach and intestine are used the systemic delivery that can comprise any applicable form outward.Use (for example) to be that intravenous, artery are interior, sheath is interior, muscle is interior, subcutaneous, muscle is interior, abdomen is interior (for example, in peritonaeum) etc., and can realize by infusion pump (outside or implantable) or any other the applicable device that is applicable to required mode of administration.
The aqueous solution that nose and other mucous membrane spray agent (such as sucking form) can comprise the purifying of reactive compound and preservative and isotonic agent preferably described preparation is adjusted to nose or the compatible pH of other mucous membrane with etc. ooze state.Or they can be the form that is suspended in the meticulous pressed powder separating in carrier gas.Can send described preparation by any applicable device or method, for example, by sprayer, atomizer, metered dose inhaler etc.
For the preparation of rectal administration, can as suppository, send with together with applicable carrier, described carrier is as cocoa butter, hydrogenated fat or hydrogenated fat carboxylic acid.
Can, by for example activating agent being incorporated to thixotroping or gel carrier, as prepared percutaneous preparation in cellulose media (methylcellulose or hydroxyethylcellulose), then resulting preparation be encapsulated in and be suitable in transcutaneous device fixing when contacting with wearer's skin.
Except composition mentioned above, preparation of the present invention can further comprise one or more auxiliary elements, and described auxiliary element is selected from such as thinner, buffer solution, flavor enhancement, adhesive, disintegrant, surfactant, thickener, lubricant, preservative (comprising antioxidant) etc.
Preparation of the present invention can have initial release or any other release profiles well known by persons skilled in the art of release immediately, sustained release, delay.
In one embodiment, the invention provides following methods: a) reduce total serum testosterone levels; B) minimizing of suffering from the luteinizing hormone (LH) in the male subject of prostate cancer by minimizing or being independent of LH hormone reduces free serum testosterone; C) about suffering from blood-serum P SA in the male subject of prostate cancer and the secondary hormonotherapy of free serum testosterone levels; D) treatment, suppress castration resistance prostate cancer (CRPC) and its symptom, reduce its incidence of disease, reduce its seriousness or suppress its progress or increase suffers from the male sex's of castration resistance prostate cancer survival rate; E) reduce the Serum PSA level in the male subject of suffering from prostate cancer; F) increase sex hormone binding globulin (SHBG) level in the male subject of suffering from prostate cancer; G) suppress to suffer from the bone dependent event (SRE) in the male subject of prostate cancer; H) reduce the level of the Bone turnover marker in the male subject of suffering from prostate cancer; I) suppress to suffer from the hot flash in the male subject of prostate cancer; And/or j) reduce the suprarenal gland generation level of androgen precurosor in the male subject of suffering from prostate cancer, it comprises uses the Orally administered composition that comprises formula IA, I to XII compound.In another embodiment, experimenter suffers from castration resistance prostate cancer (CRPC).In another embodiment, experimenter suffers from metastatic castration resistance prostate cancer (mCRPC).In other embodiment, the Orally administered composition that method utilization of the present invention comprises formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI or formula XII compound.
In one embodiment, the method of prostate cancer is treated in the reduction that the invention provides the LH level in a kind of male subject of suffering from prostate cancer by reduction or be independent of LH level, and it comprises uses the Orally administered composition that comprises formula IA, I to XII compound.In other embodiment, the invention provides the reduction of being suffered from the LH level in the male subject of prostate cancer or being independent of LH level by reduction and treat the method for prostate cancer, it comprises uses the Orally administered composition that comprises formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI or formula XII compound.In another embodiment, experimenter suffers from castration resistance prostate cancer (CRPC).In another embodiment, experimenter suffers from metastatic castration resistance prostate cancer (mCRPC).
Should understand the present invention and contain any embodiment of compound as described herein, it is called as " compound of the present invention " in some embodiments.
In one embodiment, method of the present invention can comprise with various dose and uses compound of the present invention.In one embodiment, compound of the present invention is to use with the dosage of every day 1 to 3000mg.In other embodiment, compound of the present invention is to use with following dosage: every day 1 is to 10mg, every day 3 is to 26mg, every day 3 is to 60mg, every day 3 is to 16mg, every day 3 is to 30mg, every day 10 is to 26mg, 15 to 60mg, every day 50 is to 100mg, every day 50 is to 200mg, every day 100 is to 250mg, every day 125 is to 300mg, every day 20 is to 50mg, every day 5 is to 50mg, every day 200 is to 500mg, every day 125 is to 500mg, every day 500 is to 1000mg, every day 200 is to 1000mg, every day 1000 is to 2000mg, every day 1000 is to 3000mg, every day 125 is to 3000mg, every day 2000 is to 3000mg, every day 300 to 1500mg or every day 100 are to 1000mg.In one embodiment, compound of the present invention be with every day 125mg dosage use.In one embodiment, compound of the present invention be with every day 250mg dosage use.In one embodiment, compound of the present invention be with every day 300mg dosage use.In one embodiment, compound of the present invention be with every day 500mg dosage use.In one embodiment, compound of the present invention be with every day 600mg dosage use.In one embodiment, compound of the present invention be with every day 1000mg dosage use.In one embodiment, compound of the present invention be with every day 2000mg dosage use.In one embodiment, compound of the present invention be with every day 3000mg dosage use.In another embodiment, compound is compound IV.
In one embodiment, method of the present invention can comprise with various dose and uses compound of the present invention.In one embodiment, compound of the present invention is to use with the dosage of 3mg.In other embodiment, compound of the present invention is to use with following dosage: 10mg, 30mg, 50mg, 100mg, 125mg, 200mg, 250mg, 300mg, 450mg, 500mg, 600mg, 900mg, 1000mg, 1500mg, 2000mg, 2500mg or 3000mg.In another embodiment, compound is compound IV.
In one embodiment, method of the present invention can comprise with various dose and uses compound of the present invention.In one embodiment, compound of the present invention is to use with the dosage of 0.1mg/kg/ days.In other embodiment, compound of the present invention is to use with the dosage of between 0.2 to 30mg/kg/ day or 0.2mg/kg/ days, 0.3mg/kg/ days, 1mg/kg/ days, 3mg/kg/ days, 5mg/kg/ days, 10mg/kg/ days, 20mg/kg/ days or 30mg/kg/ days.
In an embodiment of method of the present invention, provide the purposes of the Pharmaceutical composition that comprises formula IA, I to XII compound.In other embodiment, method of the present invention provides the purposes of the Pharmaceutical composition that comprises formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI or formula XII compound.
In a certain embodiment, Pharmaceutical composition is solid dosage forms.In another embodiment, Pharmaceutical composition is tablet.In another embodiment, Pharmaceutical composition is capsule.In another embodiment, Pharmaceutical composition is solution.In another embodiment, Pharmaceutical composition is transdermal patch.
In one embodiment, the composition that uses compound of the present invention or contain described compound will have effectiveness in suppressing, suppress, strengthen or stimulating the required reaction in experimenter, as will be understood by those skilled.In another embodiment, composition can further comprise other active component, and the activity of described active component is applicable to use the concrete application of compound of the present invention.
For being applied to mammal and especially people, expectation doctor will determine actual dose and treatment duration, described actual dose and treatment will be optimal concerning individuality the duration, and can according to the age of concrete individuality, body weight, heredity and/or react and and difference.
In some embodiments, any composition of the present invention will comprise the compound of the present invention that is any form as described herein or embodiment.In some embodiments, any composition of the present invention forms the compound of the present invention by being any form as described herein or embodiment.In some embodiments, composition of the present invention will mainly be comprised of the compound of the present invention that is any form as described herein or embodiment.In some embodiments, term " comprises " and refers to comprising of indicated activating agent (as compound of the present invention), and as in pharmaceuticals industry the comprising of known other activating agent and pharmaceutically acceptable carrier, excipient, softening agent, stabilizing agent etc.In some embodiments, term " mainly by ... form " refer to a kind of composition, unique active component of described composition is indicated active component, yet, can comprise for stable, preserve (etc.) preparation but be not directly involved in other compound in the therapeutic action of indicated active component.In some embodiments, term " mainly by ... form " can refer to the component of the release that contributes to active component.In some embodiments, term " by ... form " refer to that a kind of composition, described composition contain active component and pharmaceutically acceptable carrier or excipient.
Should be understood that any purposes of any compound can be used for the treatment of any disease, illness or symptom as described herein as described herein, and represent one embodiment of the invention.In one embodiment, compound is free alkali, free acid, uncharged or non-compound compound.
Present following examples so that the preferred embodiments of the invention to be more fully described.Yet they should not be interpreted as limiting broad range of the present invention.
Embodiment
Embodiment 1
The general synthesis program of formula II to XII compound and synthetic intermediate
Can be normally easily obtainable from commercial source for the organic solvent in composition described herein, surfactant and antioxidant etc.For example, PEG-300, polysorbate80, Captex tM200, Capmul tMmCM C8 can (for example) purchased from Dow Chemical Company (Midland, MI), ICI Americas, Inc (Wilmington, DE) or Abitec Corporation (Janesville, WI).
Can prepare estrogen receptor ligands described herein with various ways well known to those skilled in the art.For example, can pass through U.S. Patent Application Publication No. 2009/0062341 and United States Patent (USP) 8, synthetic method described in 158,828 is prepared estrogen receptor ligands described herein, described patent disclosure separately hereby by reference integral body be incorporated to.
N, the general of the two aryl benzamides derivatives of N – synthesized
General synthetic (Fig. 5) of diaryl aniline: by arylamine (1.5 equivalent), aryl iodide (1 equivalent), K 2cO 3the mixture of (2 equivalent), CuI (0.1 equivalent) and L-PROLINE (0.2 equivalent) mixes and is at room temperature dissolved in anhydrous DMSO.Then, stirred reaction mixture and be heated to 90 ℃ and continue 28 hours.Mixture is cooled to room temperature and water is hydrolyzed.Add EtOAc so that solution distributes.EtOAc layer is separated, with salt water washing and use anhydrous MgSO 4dry.Under reduced pressure remove solvent.Use 5%EtOAc/ hexane by rapid column chromatography method (silica gel), to come purifying solid residue to obtain corresponding diaryl aniline as eluant, eluent.
Two-(4-methoxyphenyl) amine (1a): faint yellow solid, 73% productive rate.M.p.98.6℃-99.0℃。 1H?NMR(CDCl 3,300MHz)δ6.93-6.81(m,8H),5.37(s,br,1H),3.78(s,6H)。MS?m/z228.4(M-H) +。
N-(4-methoxyphenyl)-aniline (1b): faint yellow solid, 70% productive rate.M.p.106.3-106.5℃。 1H?NMR(CDCl 3,300MHz)δ7.24-7.18(m,3H),7.08-7.06(m,2H),6.92-6.84(m,4H),5.61(s,br,1H),3.79(s,3H)。MSm/z200.1(M+H) +。
N-(4-fluorophenyl)-N-4-aminoanisole (1c): faint yellow solid, 54% productive rate.M.p.60.6℃-61.0℃。 1H?NMR(CDCl 3,300MHz)δ7.01-6.83(m,8H),3.78(s,3H)。MS?m/z217(M) +。
N-(4-benzyloxy phenyl)-N-4-aminoanisole (1d): faint yellow solid, 54% productive rate.M.p.108.0℃-108.4℃。 1H?NMR(CDCl 3,300MHz)δ7.34-7.08(m,5H),6.90-6.81(s,3H),3.78(s,3H)。MS?m/z306(M+H) +。
The general of benzamide synthesized: the mixture of aryl aniline (1 equivalent), chlorobenzoyl chloride (1.3 equivalent) and pyridine (6 equivalent) is mixed and is at room temperature dissolved in anhydrous THF.Mixture is stirred and reflux 24 hours.Reaction solution is cooled to room temperature, and is hydrolyzed by adding 2N HCl solution.Be extracted with ethyl acetate solution.By the saturated NaHCO of organic layer 3solution washing is to remove excess acid, to use anhydrous MgSO 4dry, filtration and under reduced pressure concentrated.Use EtOAc/ hexane (3/7v/v) to come purifying residue to obtain corresponding benzamide compounds by rapid column chromatography method.
The fluoro-N-of 3-(4-fluorophenyl)-4-methoxyl group-N-(4-methoxyphenyl) benzamide (2a): yellow solid, M.p.54-56 ℃. 1H?NMR(CDCl 3/TMS)δ7.24-7.11(m,4H),7.05-6.97(m,4H),6.85-6.78(m,3H),3.86(s,3H),3.79(s,3H)。MS(ESI)m/z370.1[M+H] +。
The fluoro-N of 4-, two (4-methoxyphenyl)-2-(trifluoromethyl) benzamides (2b) of N-: colorless oil, 84.2% productive rate. 1H?NMR(CDCl 3,300MHz)δ7.34-7.26(m,4H),7.09-7.01(m,3H),6.91(d,2H,J＝8.7Hz),6.87(d,2H,J＝8.7Hz),3.80(s,3H),3.71(s,3H)。MS?m/z442.1(M+Na) +。
4-methoxyl group-N-(4-methoxyphenyl)-N-(4-fluorophenyl)-benzamide (2c): white solid, 97% productive rate, M.p.133.5.0-134.5 ℃. 1H?NMR(CDCl 3,300MHz)δ8.11-6.66(m,15H),3.74(s,3H),3.73(s,3H)。MS?m/z＝384[M+H] +。
N-(4-methoxyphenyl)-N-(4-benzyloxy phenyl)-2-naphthalene amino acid (2d): white solid, 58% productive rate.M.p.174.9-175.5℃。 1H?NMR(CDCl 3,300MHz)δ8.04(s,1H),7.77-7.74(m,2H),7.64-7.61(m,1H),7.51-7.43(m,4H),7.40-7.31(m,4H),7.13-7.10m,4H),6.88-6.78(m,4H),4.99(s,2H),3.74(s,3H)。MS?m/z460(M+H) +。
The fluoro-N of 4-, two (4-methoxyphenyl)-2-(trifluoromethyl) benzamides (2e) of N-: colorless oil, 84.2% productive rate. 1H?NMR(CDCl 3,300MHz)δ7.34-7.26(m,4H),7.09-7.01(m,3H),6.91(d,2H,J＝8.7Hz),6.87(d,2H,J＝8.7Hz),3.80(s,3H),3.71(s,3H)。MS?m/z442.1(M+Na) +。
Use BBr 3make the general procedure of heterocyclic carbamate derivatives demethylation: methoxy benzamide compound is dissolved in to anhydrous CH 2cl 2in.At 0 ℃, dropwise add BBr 3(1.0MCH 2cl 2solution).Reaction solution is slowly heated to room temperature and at room temperature stirs and spend the night.Mixture is cooled in ice bath to 0 ℃ and be hydrolyzed by adding water.Add EtOAc so that solution distributes.Organic layer is separated, use EtOAc aqueous layer extracted.Organic layer is used to salt water washing and used anhydrous MgSO 4dry.Under reduced pressure remove solvent.Use CH 3oH/CH 2cl 2(1/9v/v) by rapid column chromatography method, come purifying residue to obtain corresponding phenolic compound.
The fluoro-N of 4-, two (4-hydroxy phenyl)-2-(trifluoromethyl) benzamides (3a) of N-: white solid, 92.5% productive rate. 1H?NMR(DMSO-d 6,300MHz)δ9.55(s,1H),9.53(s,1H),7.69-7.58(m,2H),7.46-7.39(m,1H),7.18(d,2H,J＝8.7Hz),6.93(d,4H,J＝8.7Hz),7.03(d,2H,J＝8.4Hz),6.78(d,2H,J＝8.7Hz),6.57(d,2H,J＝8.7Hz)。MS?m/z392.1(M+H) +。
Following compound is synthesize as described above and in table 1, characterize and sum up: N, two (4-the hydroxy phenyl)-4-propyl benzamides (II) of N-; The fluoro-N-of 3-(4-fluorophenyl)-4-hydroxy-n-(4-hydroxy phenyl) benzamide (IV); N, two (the 4-hydroxy phenyls)-2 of N-, 3-dimethyl benzamide (V); The fluoro-4-hydroxy-n of 3-, two (4-the hydroxy phenyl)-benzamides (VII) of N-; The fluoro-4-hydroxy-n of 3--(4-hydroxy phenyl)-N-phenylbenzamaide (XI); And the fluoro-N of 3-, two (4-the hydroxy phenyl)-2-methyl benzamides (XII) of N-.
The general procedure that is used for the debenzylation of benzyloxy phenyl-benzamide: benzyloxy phenyl-benzamide compounds is dissolved in the EtOH of 250mL hydrogenation bottle Pd/C powder (5mol%) is added into solution.Reaction vessel is mounted to hydrogenation apparatus under 20psi pressure hydrogen.By TLC, monitor reaction until starting material disappears.Then, under reduced pressure remove solvent.With hexane/EtOAc=3/2v/v, by rapid column chromatography method, come purifying residue to obtain required product.
Following compound is synthesize as described above and in table 1, characterize and sum up: N, two (4-the hydroxy phenyl)-2-naphthalene amino acids (VI) of N-.
General procedure for the reduction of the benzamide of deprotection: benzamide compounds is at room temperature dissolved in to the anhydrous THF of 20mL.At room temperature under argon, via syringe, add H 3b (SMe 2).Stirring reaction solution and be heated to reflux to continue 6 hours.Then, by add the MeOH of 10mL at 0 ℃, come cancellation to react.Under reduced pressure remove solvent.Make residue stand rapid column chromatography method (silica gel, CH 2cl 2/ MeOH=9/1v/v) to obtain required product.
Following compound is synthesize as described above and in table 1, characterize and sum up: 4,4'-(2,3-dimethyl benzyl azane, two bases) biphenol (III); 4-((4-fluorophenyl) (4-hydroxy phenyl) amino) phenol (VIII).
The general of O-(2-piperidin-1-yl ethyoxyl)-benzamide and analog synthesized: the solution to the benzamide analogs that contains hydroxy phenyl (1 equivalent) in acetone adds K 2cO 3(3 equivalent) and N-chloroethyl-piperidine hydrochlorate (1.2 equivalent).Solution is heated to reflux and continues 6 hours.Solution is evaporated to dry.Residue is hydrolyzed by adding water, and is then extracted with ethyl acetate.Organic layer is separated and use anhydrous MgSO 4dry.Under reduced pressure remove solvent.With methylene chloride/methanol=9/1v/v, by rapid column chromatography method, come purifying residue to obtain required compound.By will be in Et 2hCl in O is added into the methanol solution of compound, then evaporating solvent is prepared hydrochloride.
Following compound is synthesize as described above and in table 1, characterize and sum up: the fluoro-N-of 4-(4-hydroxy phenyl)-N-(4-(2-(piperidin-1-yl) ethyoxyl) phenyl)-2-(trifluoromethyl) benzamide (IX); With the fluoro-N-of 4-(4-hydroxy phenyl)-N-(4-(2-(piperidin-1-yl) ethyoxyl) phenyl)-2-(trifluoromethyl) benzamide hydrochloride salt (X), it is the HCl salt of IX.
The physical characterization of table 1. formula II to XII compound
Embodiment 2
Synthetic (Fig. 6) of formula IV compound.
Synthesizing of the fluoro-N-of step 1:4-(4-methoxyphenyl) aniline (1c).
By 4-fluoroaniline (78.63g, 0.708mol), 4-iodanisol (138.00g, 0.590mol), anhydrous K 2cO 3(122.23g, 0.884mol), CuI (11.23g, 58.96mmol) and the mixture of L-PROLINE (13.58g, 0.118mol) in being equipped with the dry 1L tri-neck round-bottomed flasks of stirring rod, reflux condenser and argon entrance, mix.At room temperature add anhydrous DMSO (300mL).Stirred reaction mixture and be heated to 90 ℃ and continue 20 hours under argon.Then, mixture being cooled to room temperature and water (300mL) is hydrolyzed.Add EtOAc (200mL) so that solution distributes.Separated EtOAc layer.By 100mL EtOAc aqueous layer extracted.EtOAc is laminated also, use salt solution (2 * 100mL) washs and uses anhydrous MgSO 4(50g) dry.Under reduced pressure remove solvent.By rapid column chromatography method (silica gel, hexane/EtOAc=9/1v/v), come the brown oily residue of purifying to obtain being the fluoro-N-of 4-(4-methoxyphenyl) aniline (1c) of yellow solid product form, 99.70g, 77.8% productive rate.M.p.46-48℃.MS(ESI)m/z218.1[M+H] +, 1H?NMR(DMSO-d 6,300MHz)δ7.77(bs,1H),7.03–6.98(m,4H),6.93–6.82(m,4H),3.70(s,3H)。
Synthesizing of the fluoro-N-of step 2:3-(4-fluorophenyl)-4-methoxyl group-N-(4-methoxyphenyl) benzamide (2a).
By the fluoro-N-of 4-(4-methoxyphenyl) aniline (1c) (90.78g, 0.418mol) mix and be dissolved in the anhydrous THF (200mL) in the dry 1L tri-neck round-bottomed flasks that are equipped with stirring rod, reflux condenser and argon entrance with the fluoro-4-methoxy benzoyl chloride of 3-(94.55g, 0.501mol).At room temperature under argon, via syringe, add anhydrous pyridine (132.22g, 1.672mol).Stirred reaction mixture and be heated to reflux and spend the night.Then, reactant mixture be cooled to room temperature and filter to remove pyridiniujm.Concentrated solution is to remove THF solvent.Remaining grease is used to 200mL2N HCl solution washing and extracted with ethyl acetate (2 * 200mL).By the saturated Na of organic layer merging 2cO 3the aqueous solution (150mL) washing is to remove excessive benzene formyl chloride and acid, to use MgSO 4(50g) dry, filtration and under reduced pressure concentrated to obtain grease.Use CH 2cl 2/ acetone (50/1v/v) comes purifying residue to obtain being the pure corresponding benzamide compounds of yellow solid shape with silica gel by rapid column chromatography method.M.p.54-56℃。MS(ESI)m/z370.1[M+H] +, 1H?NMR(CDCl 3/TMS)δ7.24-7.11(m,4H),7.05-6.97(m,4H),6.85-6.78(m,3H),3.86(s,3H),3.79(s,3H)。
Synthesizing of the fluoro-N-of step 3:3-(4-fluorophenyl)-4-hydroxy-n-(4-hydroxy phenyl) benzamide (IV).
At room temperature under argon, the fluoro-N-of compound 3-(4-fluorophenyl)-4-methoxyl group-N-(4-methoxyphenyl) benzamide (2a) (138.0g, 0.374mol) is dissolved in to anhydrous CH 2cl 2(600mL) in.At 0 ℃, in ice bath, under argon, via syringe, under agitation dropwise add BBr 3(374.75g, 1.496mol).Reaction solution is at room temperature stirred and spent the night.Then, under agitation by solution to 1L frozen water.Slurry mix is at room temperature stirred 2 hours.By white depositions filtration, water (2 * 100mL) washing and dry under vacuum.By CH 2cl 2layer is separated, use anhydrous MgSO 4(50g) be dried, filter and be under reduced pressure concentrated into dry.By white depositions and from CH 2cl 2the residue of solution merges and by rapid column chromatography method (silica gel, CH 2cl 2/ acetone/MeOH=90/7/3v/v/v) purifying, to obtain cervine solid, is recrystallized described solid twice to obtain white crystalline solid, 104.0g, 81.6% productive rate from hot EtOAc/ hexane solution.M.p.110-112℃。MS(ESI)m/z364.1[M+Na] +, 1H?NMR(DMSO-d 6)δ10.14(bs,1H),9.71(bs,1H),7.25-7.11(m,5H),7.05-6.99(m,3H),6.78(t,J＝8.6Hz,1H),6.68(d,J＝8.7Hz,2H)。
Embodiment 3
Synthetic (Fig. 7) of formula VI compound
Synthesizing of 4-(benzyloxy)-N-(4-methoxyphenyl) aniline (1d).
By 4-benzyloxy-aniline (16.6g, 83.31mmol), 4-iodanisol (15.0g, 64.09mmol), K 2cO 3the mixture of (17.72g, 128.18mmol), CuI (1.22g, 6.41mmol) and L-PROLINE (1.48g, 12.82mmol) mixes and is at room temperature dissolved in anhydrous DMSO (120mL).Then, stirred reaction mixture and be heated to 90 ℃ and continue 48 hours.Mixture is cooled to room temperature and water is hydrolyzed.Add EtOAc so that solution distributes.EtOAc layer is separated, with salt water washing, use anhydrous MgSO 4dry.Under reduced pressure remove solvent.Use EtOAc/ hexane (1/9v/v) to come purifying solid residue to obtain being the corresponding diaryl aniline of yellow solid, 9.8g, 50% productive rate by rapid column chromatography method (silica gel).M.p.108.0-108.4℃。 1H?NMR(CDCl 3,300MHz)δ7.34-7.25(m,5H),6.90-6.81(m,8H),5.02(s,2H),3.78(s,3H)。MS?m/z306(M+H) +。
Synthesizing of N-(4-benzyloxy phenyl)-N-(4-methoxyphenyl)-2-naphthalenecarboxamide (2d).
By the 4-of monovalent (benzyloxy)-N-(4-methoxyphenyl) aniline (0.80g, 2.62mmol) with the 2-naphthoyl chloride (0.75g of 1.5 equivalents, the pyridine (0.83g, 10.48mmol) of 3.93mmol) He 4 equivalents mixes in being equipped with the dry three neck round-bottomed flasks of magnetic stirring bar and reflux condenser.Mixture is dissolved in anhydrous THF (30mL) and is heated to reflux and continue 20 hours.Reaction solution is cooled to room temperature and filtration.Under reduced pressure remove solvent.
With EtOAc/ hexane (3/7v/v), with silica gel, by rapid column chromatography method, come purifying residue with the pure corresponding naphthalenecarboxamide compound of the solid shape that obtains being white in color, 0.70g, 58% productive rate.M.p.174.9-175.5℃。 1H?NMR(CDCl 3,300MHz)δ8.04(s,1H),7.77-7.74(m,2H),7.64-7.61(m,1H),7.51-7.43(m,4H),7.40-7.31(m,4H),7.13-7.10(m,4H),6.88-6.78(m,4H),4.99(s,2H),3.74(s,3H)。MS?m/z460(M+H) +。
N, two (4-the hydroxy phenyl)-2-naphthalene amino acids (VI) of N-synthetic.
At room temperature compound N-(4-benzyloxy phenyl)-N-(4-methoxyphenyl)-2-naphthalenecarboxamide (2d) (0.50g, 1.09mmol) is dissolved in to anhydrous CH 2cl 2(30mL) in.At room temperature via syringe, under agitation dropwise add BBr 3(the 1.0M CH of 3.26mL 2cl 2solution, 3.26mmol).Reaction solution is at room temperature stirred and spent the night.Mixture is cooled in ice bath to 0 ℃ and be hydrolyzed by adding water.Add EtOAc so that solution distributes.Organic layer is separated; By twice of EtOAc aqueous layer extracted.Organic layer is merged, uses salt water washing and use anhydrous MgSO 4dry.In vacuum, go down to desolventize.Use CH 3oH/CH 2cl 2(1/9v/v) with silica gel, by rapid column chromatography method, come purifying residue with the pure required phenolic compound of the solid shape that obtains being white in color, 0.27g, white solid, 70% productive rate.M.p.264.3-265.2 ℃ (decomposition). 1H?NMR(DMSO-d 6,500MHz)δ9.46(s,2H),7.98(s,1H),7.85-7.75(m,2H),7.75-7.73(m,2H),7.54-7.48(m,2H),7.45-7.43(m,1H),7.05(s,4H),6.66(s,4H)。MS?m/z356(M+H) +。
Embodiment 4
Synthesizing of formula VIII compound.
Synthesizing of 4-((4-fluorophenyl) (4-hydroxybenzyl) amino) phenol (VIII).
Compound N-(4-fluorophenyl)-4-hydroxy-n-(hydroxy phenyl) benzamide (0.30g, 0.93mmol) is at room temperature dissolved in the anhydrous THF of 20mL.At room temperature under argon, via syringe, add H 3b (SMe 2) (the 2M THF solution of 1.86mL, 3.71mmol).Stirring reaction solution and be heated to reflux to continue 6 hours.Then, by add the MeOH of 10mL at 0 ℃, come cancellation to react.Under reduced pressure remove solvent.Make residue stand rapid column chromatography method (silica gel, CH 2cl 2/ MeOH=9/1v/v) to obtain yellow oil, 0.26g, 92% productive rate. 1H?NMR(DMSO-d 6,500MHz)δ9.29(s,1H),9.24(s,1H),7.09(d,2H,J＝8.3Hz),6.98(d,2H,J＝9.0Hz),6.94-6.91(m,2H),6.73(d,2H,J＝9.0Hz),6.68-6.64(m,4H),4.70(s,2H)。MS?m/z307.8(M-H) -。
Embodiment 5
Synthetic (Fig. 8) of formula IX and X compound.
Synthesizing of diaryl aniline.By arylamine (1.5 equivalent), aryl iodide (1 equivalent), K 2cO 3the mixture of (2 equivalent), CuI (0.1 equivalent) and L-PROLINE (0.2 equivalent) mixes and is at room temperature dissolved in anhydrous DMSO.Then, stirred reaction mixture and be heated to 90 ℃ and continue 28 hours.Mixture is cooled to room temperature and water is hydrolyzed.Add EtOAc so that solution distributes.EtOAc layer is separated, with salt water washing, use anhydrous MgSO 4dry.Under reduced pressure remove solvent.Use EtOAc/ hexane (3/7v/v) by rapid column chromatography method (silica gel), to come purifying solid residue to obtain corresponding diaryl aniline as solvent.Two-(4-methoxyphenyl) amine (1a): faint yellow solid, 73% productive rate. 1H?NMR(CDCl 3,300MHz)δ6.93-6.81(m,8H),5.37(s,br,1H),3.78(s,6H)。MS?m/z228.4(M-H) +。
The fluoro-N of 4-, two (4-methoxyphenyl)-2-(trifluoromethyl) benzamides (2e) of N-synthetic.
By 1 equivalent two-(4-methoxyphenyl) amine (1a) (0.73g, 3.18mmol) with the fluoro-2-trifluoromethyl benzoyl chloride of the 4-(0.87g of 1.2 equivalents, the pyridine (1.51g, 19.08mmol) of 3.82mmol) He 6 equivalents mixes in being equipped with the dry three neck round-bottomed flasks of magnetic stirring bar and reflux condenser.Mixture is dissolved in anhydrous THF (20mL) and is heated to 90 ℃ and continue 20 hours.Reaction solution is cooled to room temperature and filtration.Under reduced pressure remove solvent.With EtOAc/ hexane (3/7v/v), with silica gel, by rapid column chromatography method, come purifying residue to obtain being the pure corresponding benzamide compounds of colorless oil form, 1.12g, 84.2% productive rate. 1H?NMR(CDCl 3,300MHz)δ7.34-7.26(m,4H),7.09-7.01(m,3H),6.91(d,2H,J＝8.7Hz),6.87(d,2H,J＝8.7Hz),3.80(s,3H),3.71(s,3H)。MS?m/z442.1(M+Na) +。
The fluoro-N of 4-, two (4-hydroxy phenyl)-2-(trifluoromethyl) benzamides (3a) of N-synthetic.
By the fluoro-N of compound 4-, two (4-methoxyphenyl)-2-(trifluoromethyl) benzamides (2e) (1.00g, 2.38mmol) of N-are at room temperature dissolved in anhydrous CH 2cl 2(30mL) in.At room temperature via syringe, under agitation dropwise add BBr 3(the 1.0M CH of 10mL 2cl 2solution, 10.0mmol).Reaction solution is at room temperature stirred and spent the night.Mixture is cooled in ice bath to 0 ℃ and be hydrolyzed by adding water.Add EtOAc so that solution distributes.Organic layer is separated; By twice of EtOAc aqueous layer extracted.Organic layer is merged, uses salt water washing and use anhydrous MgSO 4dry.In vacuum, go down to desolventize.Use CH 3oH/CH 2cl 2(1/9v/v) with silica gel, by rapid column chromatography method, come purifying residue with the pure required phenolic compound of the solid shape that obtains being white in color, 0.86g, 92.5% productive rate. 1H?NMR(DMSO-d 6,300MHz)δ9.55(s,1H),9.53(s,1H),7.69-7.58(m,2H),7.46-7.39(m,1H),7.18(d,2H,J＝8.7Hz),6.93(d,4H,J＝8.7Hz),7.03(d,2H,J＝8.4Hz),6.78(d,2H,J＝8.7Hz),6.57(d,2H,J＝8.7Hz)。MS?m/z392.1(M+H) +。
The fluoro-N-of 4-(4-hydroxy phenyl)-N-[4-(2-piperidin-1-yl)-ethyoxyl) phenyl]-2-(trifluoromethyl) benzamide (IX) synthetic.
To the fluoro-N of 4-, the solution of two (4-hydroxy phenyl)-2-(trifluoromethyl) benzamides (3a) (0.61g, 1.56mmol) of N-in acetone adds K 2cO 3(1.29g, 9.36mmol) and N-chloroethyl-piperidine hydrochlorate (0.34g, 1.87mmol).Solution is heated to reflux and continues 20 hours.Solution is evaporated to dry.By flash chromatography method (silica gel; Methylene chloride/methanol=9/1v/v) come purifying residue with the required compound of the solid shape that obtains being white in color, 0.45g, 57.7% productive rate. 1H?NMR(DMSO-d 6,300MHz)δ9.57(s,1H),7.71-7.68(m,2H),7.47-7.44(m,1H),7.28(d,1H,J＝9.0Hz),7.18(d,1H,J＝8.7Hz),7.13(d,1H,J＝8.7Hz),7.05(d,1H,J＝8.4Hz),6.97(d,1H,J＝9.0Hz),6.80-6.76(m,2H),6.57(d,1H,J＝87.Hz),4.06(t,1H,J＝6.0Hz),3.93(t,1H,J＝6.0Hz),2.66(t,1H,J＝5.7Hz),2.55(t,1H,J＝5.4Hz),2.44(s,2H),2.36(s,2H),1.49-1.37(m,6H)。MS?m/z501.0(M-H) -。
By will be in Et 2hCl in O is added into the methanol solution of compound, then evaporating solvent is prepared hydrochloride (X).
Embodiment 6
Estrogen receptor binding affinity, activator and antagonist activities
With [2,4,6,7- 3h (N)]-estradiol ([ 3h] E2) GST of (natural high affinity ER part) and bacterial expression merges ER-α or ER-beta ligands in conjunction with territory (LBD) albumen, with external competitive radioligand in conjunction with the ER binding affinity of measuring compound.
Method
To recombinate ER-α or ER-β with [ 3h]E 2combine to measure [ 3h]E 2equilibrium dissociation constant (K d).At 4 ℃, at the unlabelled E that has and do not have high concentration 2situation under, with increase concentration [ 3h]E 2hatch protein 18h to determine total binding and non-specific binding.Deduct non-specific binding and determine E by nonlinear regression 2k d(ER α: 0.71nM; ER β: 1.13nM).In addition, make ER-α and ER-β LBD saturated required [ 3h]E 2concentration be defined as 4-6nM.
Use condition described above with [ 3h]E 2(5.7nM) hatch the compound (scope: 10 of the concentration of increase with ER LBD -11to 10 -6m).After hatching, at Unifilter-96 collector (PerkinElmer), above with GF/B filter collecting board and by ice-cold buffer B (50mM Tris, pH7.2), wash three times.At room temperature dry filter plate, is then added into each hole by 35 μ lMicroscint-O mixtures, and filter plate is sealed with TopSeal-A.Use for 3h is arranged in Microscint mixture (PerkinElmer) in NXT microtest plate scintillation counter, radioactivity is counted.
By deducting [ 3h]E 2non-specific binding (by with 10 -6the unlabelled E of M 2hatch to measure) and the percentage that it is expressed as to specific binding in the situation that not there is not test compounds recently determine [ 3h]E 2specific binding under the compound of every kind of concentration.Definite making [ 3h]E 2specific binding reduce the concentration (IC of 50% compound 50).Then by following formula, calculate the equilibrium association constant (K of compound i): K i=K d* IC 50/ (K d+ L), K wherein dbe [ 3h]E 2equilibrium dissociation constant (ER-α=0.71nM; ER-β=1.13nM), and L be [ 3h]E 2concentration (ER-α: 5.7nM; ER-β: 5.7nM).
Result
In conjunction with measure to disclose part with from 3.75nM to the variable concentrations that is greater than 1000nM scope in conjunction with ER-α and ER-β, and selectivity scope is to be that Isoform selective is to non-Isoform selective from compound.In table 2, list the result of representative compound.
The combination result of the selected compound of table 2..
Compound IV is bonded to ER α and ER β with nanomole affinity.With [2,4,6,7- 3h (N)]-estradiol ([ 3h]E 2) GST of (natural high affinity ER part) and bacterial expression merges ER α or ER beta ligands in conjunction with territory (LBD) albumen, with external competitive radioligand in conjunction with the ER binding affinity of measuring compound IV.In this is measured, the ER α of compound IV and ER β binding affinity (K ivalue) be respectively 21.7 ± 1.7nM (n=3) and 15.2 ± 4.1nM (n=3).When ER is combined, compound IV causes the molecular events of series of complex, and described event causes target gene related in pharmacological reaction with expression or the inhibition of tissue selectivity mode.In transient transfection is measured, compound IV is ER α and ER beta-agonists, and it has the effect of the transcriptional activation of stimulation ER α-mediation of comparing larger proof with Er β.And estradiol activates ER α and ER β, wherein ER α is had to 5.1 times of larger selectivity, compound IV shows 49.0 times of selectivity for ER α.Therefore, compound IV has than the selectivity of large relative 9.7 times of ER β for ER α in trans-activation effect (being normalized to estradiol value) relatively.In addition in the transcriptional activation stimulating at estradiol (1nM),, do not observe the antagonist action up to the compound IV of 10 μ M concentration.Although many steroids parts and other nuclear hormone receptor cross reaction, the effect of compound IV has specificity to ER α and ER β.In transcriptional activation is measured, with activator and antagonist mode, the cross reactivity for people's isoform, liver X receptor (LXR), peroxisome proliferation-activated receptors (PPAR-α and PPAR-γ) and the retinoids X acceptor (RXR-α) of the rat isoform for glucocorticoid receptor (GR), mineralcorticoid receptor (MR), progesterone receptor (PR), androgen receptor (AR) and farnesol X acceptor (FXR) screens compound IV.Compound IV does not show any activator or antagonist activities in any these are measured, thereby supports to draw a conclusion: compound IV not with these nuclear hormone receptor superfamily member cross reactions in function.
Embodiment 7
The transactivation of selected compound
With activator pattern and antagonist pattern, carry out trans-activation mensuration to differentiate that described compound is activator, antagonist or part.
Method
Rat estrogen receptor from rat ovarian cdna (ER-α and ER-β) is cloned in pCR3.1 plasmid vector main chain.Check order to determine and do not have any sudden change.By HEK-293 cell with in each hole of 24 orifice plates 100,000 cell be seeded in Du Shi MEM (Dulbecco ' s Minimal Essential Media, in the hyclone of DMEM)+5% charcoal treatment (charcoal-stripped fetal bovine serum, csFBS).Use lipofection amine (Invitrogen, Carlsbad, CA), with 0.25 μ g ERE-LUC, 0.02 μ g CMV-LUC (renilla luciferase (renilla luciferase)) and 12.5ng rat ER-α or 25ng rat ER-β, carry out transfectional cell.After transfection by cell by the compound of variable concentrations or the combined treatment of compound and estradiol 24 hours to determine antagonistic activity.Within 48 hours after transfection, carry out luciferase assay.
Result
The screening of compound of the present invention in trans-activation system discloses described compound and belongs to all three classes, i.e. activator, antagonist and partial agonist.In table 3, provide the example of activator and antagonist.Trans-activation result is mated extremely well with the combination result of Isoform selective.
Table 3 provides the EC of the compound of selections more of the present invention 50and IC 50transactivation value.
The transactivation of table 3. alternative cpd of the present invention (activator and antagonist)
Embodiment 8
Testosterone compacting in rhesus macaque
During studying, according to USDA guide, raise the complete Rhesus Monkey (n=2) of sexual gland in two years old age, make it freely obtain primate diet and water (except fasting before oral dose is used).Give the animal oral formula IV compound in the microemulsion medium of Tween80/ deionized water of raising by force dosage of 30mg/kg once a day, continuous 7 days.Before using, the oral dose of the 1st day (baseline), the 3rd day, the 4th day, the 5th day, the 6th day and the 7th day extracts blood serum sample by venipuncture.In the situation that combining or not combining HPLC method, use respectively enzyme immunoassay (EIA) (EIA) method to quantize testosterone and total androgen.After with formula IV compounds for treating 6 days, for testosterone and total androgen (testosterone/dihydrotestosterone), time dependence minimizing is obvious.Formula IV compound respectively in #1 animal and #3 animal with respect to baseline value (referring to the solid line in Fig. 1; Table 4) compacting testosterone levels reaches 58% and 64%.Similarly, compare with baseline value, in #1 animal and #3 animal, total androgen levels is all pressed 56% (referring to the dotted line in Fig. 1; Table 4).
Consistent with the oestrogenic hormone feedback of hypophysis-testis axis in the male sex, these results prove after repeating the formula IV compound of oral dose (30mg/kg), the firm pharmacological reaction of suppressing for serum hormone (testosterone and total androgen) in complete non-human primates (rhesus macaque).
Testosterone levels in the serum of the complete male monkey of the Orally administered formula IV compound of table 4. 30mg/kg every day (the 0th day the first dosage) and total androgen levels
Embodiment 9
LH level in rat and the compacting of testosterone hormonal readiness
Carry out dose-response research effect to the LH compacting in (ORX) male rat of complete male rat and male castration with assessing compound IV in body.In intact animal and ORX animal, when comparing with corresponding contrast, the compound IV of every day >=10mg/kg dosage is suppressed LH level significantly.(at FSH, observe the compacting of model identical aspect horizontal.) LH compacting causes testosterone levels to be firmly reduced to lower than quantizing limit (BLOQ) (it is 0.08ng/mL), reduce with the weight of prostate, seminal vesicle and musculus levator ani (levator ani) weight muscle, because these are height Androgen-dependent sexual organs.In intact animal, notice that the dose dependent of the weight of these target organs reduces, wherein seminal vesicle and musculus levator ani muscle weight are reduced to the level of castration contrast.Although weight of prostate significantly reduces in intact animal, these values do not reach the level of castration contrast.Result is summarised in following table 6.
Materials and methods:
The male Sprague-Dawley rat of great about 200g was maintained under 12 little time/dark cycles, and it can arbitrarily obtain food (2016Teklad Global16% protein rodent diet, Harlan, Madison, WI) and water.Animal scheme obtains the care of animal of Tennessee State university and audit and the approval of the committee of use.
Test article for this research are weighed and be dissolved in the 10%DMSO (Fisher) diluting with PEG300 (Acros Organics, NJ) to prepare suitable dosage particles.For this research, by body weight is random, select 60 (60) male Sprague-Dawley rats, and be dispensed to one of 12 treatment groups (n=5 animal/group).In table 5, list treatment group.Animal is raised with the group of 2 to 3 animals of every cage.Control group (complete with (ORX) male castration) is used medium every day.By compound IV with 0.3,1,3,10 and the dosage of 30mg/kg/ days via hypodermic injection (200 μ L), be applied to close set and ORX group.
After 14 days dosage regimens, by animal, in anesthesia, (ketamine/plug draws piperazine, puts to death and record body weight under 87:13mg/kg).In addition, remove ventral prostate, seminal vesicle and musculus levator ani, remove outside organization and weigh separately.Organ weight is normalized to body weight and is expressed as the percentage of complete contrast.Under isoflurane anesthesia, from abdominal aorta, collect blood and make it condense into piece.By centrifugation serum and be stored at-80 ℃, measure subsequently hormone serum level.According to the guidance of manufacturer, by rat pituitary Luminex, measure (Millipore, Billerica, MA) and measure serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) concentration.The quantification lower limit of this mensuration is 3.2pg/mL to LH and is 32pg/mL to FSH.By testosterone EIA (Alpco Diagnostics, Salem, NH), measure testosterone, wherein LLOQ is 0.08ng/mL.From the analysis of cell mean, omit lower than the serum hormone value that quantizes lower limit (BLOQ).Therefore the report value that, has LH and T in the group of sample BLOQ is higher than real value.This analytical method provides the most conservative estimation of LH and T compacting.Fisher least significant difference test is for more indivedual dosage groups and complete and ORX vehicle control group.Significance is defined as P-value <0.05 by priori.
Table 5. treatment group
Group Sexual gland state Dosage (mg/kg/ days) Test article
1 Complete -- Medium
2 ORX -- Medium
3 Complete 0.3 Compound IV
4 Complete 1 Compound IV
5 Complete 3 Compound IV
6 Complete 10 Compound IV
7 Complete 30 Compound IV
8 ORX 0.3 Compound IV
9 ORX 1 Compound IV
10 ORX 3 Compound IV
11 ORX 10 Compound IV
12 ORX 30 Compound IV
Luteinizing hormone level (table 6) in intact rats and ORX rat
LH level (mean value ± SD) in complete vehicle control group and ORX vehicle control group is respectively 1.46 ± 0.64 and 11.1 ± 3.9ng/mL.Compound IV dose dependent ground reduces the LH level in intact animal, with every daily dose >=3mg/kg, reaches statistically and reduces significantly.Respectively 0.3,1,3,10 and the dosage of 30mg/kg/ days after, the LH level in the complete animal of compound IV treatment is 0.863 ± 0.384,0.704 ± 0.530,0.395 ± 0.302,0.226 ± 0.165 and 0.236 ± 0.176ng/mL.LH level during ORX is male is also treated significantly and is reduced by compound IV.Respectively 0.3,1,3,10 and the dosage of 30mg/kg/d after, in ORX animal, LH level is 15.4 ± 2.9,13.5 ± 2.2,6.5 ± 5.6,0.425 ± 0.135 and 0.368 ± 0.119ng/mL.Result diagram in Figure 10 A presents.
In the rat of intact rats and male castration, the compound IV of the dosage of 10mg/kg/ days is significantly suppressed luteinizing hormone (LH) level, thereby causes the castration serum levels of endogenous testosterone.
Follicle stimulating hormone level (table 6) in intact rats and ORX rat
Serum FSH level in complete vehicle control group and ORX vehicle control group is respectively 20.9 ± 8.5 and 93.5 ± 13.8ng/mL.In intact animal, compound IV dose dependent ground reduces FSH level, wherein under the dosage of >=10mg/kg/ days, observes remarkable reduction.Respectively 0.3,1,3,10 and the dosage of 30mg/kg/ days after, the FSH level in the intact animal of compound IV treatment is 17.3 ± 6.4,15.7 ± 7.3,18.4 ± 7.7,9.2 ± 4.0 and 6.3 ± 1.8ng/mL.Respectively 0.3,1,3,10 and the dosage of 30mg/kg/ days after, in ORX animal, LH level is 115 ± 17,114 ± 22,65.2 ± 31.9,27.6 ± 8.2 and 15.1 ± 4.1ng/mL.Result diagram in Figure 10 B presents.
Testosterone levels in intact rats and ORX rat
Level of serum testosterone in complete vehicle control group is 2.4 ± 1.1ng/mL.The quantification lower limit of T is 0.08ng/mL.The value that is less than 0.08ng/mL is designated as lower than quantizing limit (BLOQ).In intact animal, formula IV compound dosage dependence ground reduces T level, wherein under the dosage of every day >=3mg/kg, observes remarkable reduction.Respectively after the dosage of every day 0.3,1,3,10 and 30mg/kg, with the testosterone levels in the intact animal of formula IV compounds for treating be 2.6 ± 1.7,1.6 ± 1.0,0.7 ± 0.4, BLOQ and BLOQ ng/mL.In ORX animal, for all groups and the group of medium treatment with compound IV treatment, T level is BLOQ.The result of intact animal diagrammatically presents (for diagram object, limit place represents BLOQ value in quantification) in Figure 10 C (and Fig. 2).
As presented in Fig. 9, by after 24 hours, 72 hours and 168 hours with the dosage administered compound IV of 3mg/kg, 10mg/kg and 300mg/kg measure serum testosterone in complete male rat fast and effectively compacting.
Organ weight's (table 6)
Measure prostate, seminal vesicle and musculus levator ani weight to confirm the compacting of T.In Figure 10 D, 10E and 10F, present respectively organ weight (mean value ± SD).The dose dependent of observing prostate, seminal vesicle and musculus levator ani weight in the intact animal with compound IV treatment reduces.Respectively 0.3,1,3,10 and the dosage of 30mg/kg/ days after, the weight of prostate in intact animal is 84.0 ± 19.2,75.2 ± 20.7,68.2 ± 8.1,45.1 ± 20.0 and 43.6 ± 8.8.Respectively 0.3,1,3,10 and the dosage of 30mg/kg/ days after, the weight of prostate in ORX animal is 19.0 ± 4.2,17.4 ± 3.4,19.6 ± 6.7,22.9 ± 5.4 and 20.6 ± 2.1.Respectively 0.3,1,3,10 and the dosage of 30mg/kg/ days after, the seminal vesicle weight in intact animal is 76.2 ± 7.8,66.3 ± 27.2,51.8 ± 28.5,19.1 ± 7.0 and 17.9 ± 3.3.Respectively 0.3,1,3,10 and the dosage of 30mg/kg/ days after, the seminal vesicle weight in ORX animal is 12.2 ± 1.3,16.6 ± 5.4,16.5 ± 4.8,13.3 ± 1.9 and 12.9 ± 2.1.Respectively 0.3,1,3,10 and the dosage of 30mg/kg/ days after, the musculus levator ani weight in intact animal is 86.9 ± 10.0,82.1 ± 12.1,65.2 ± 4.4,57.8 ± 11.2 and 58.1 ± 4.7.Respectively 0.3,1,3,10 and the dosage of 30mg/kg/ days after, the musculus levator ani weight in ORX animal is 54.5 ± 6.6,49.6 ± 7.0,53.6 ± 10.0,51.1 ± 4.9 and 49.2 ± 4.2.
LH compacting and organ weight's data are summarised in table 6.
Table 6. formula IV compound is to acting in serum hormone and organ weight's body
acontrast complete medium, P<0.05. bcontrast ORX medium, P<0.05
In the rat of intact rats and male castration, the compound IV of the dosage of 10mg/kg/ days is significantly suppressed luteinizing hormone (LH) level, thereby causes the castration serum levels of endogenous testosterone.
Compound IV can not increase the propagation of external prostatic epithelium cancer cell.In mechanism, compound IV provides and is better than existing therapy as several key advantage of gonadotropin-releasing hormone (GRH) (GnRH) activator and GnRH antagonist.Compound IV has specificity to estrogen receptor, and oral biology is available in rat, dog, monkey and people.Compare with GnRH antagonist with the GnRH activator that causes hot flash and significant bone-loss and increase the risk of fracture, compound IV weakens the hot flash of morphine abstinence syndrome induction in rat and in the distal femoral of rat, maintains trabecular bone quality and BMD completely, even if farthest suppressing under the dosage of LH and serum testosterone.
Embodiment 10
The recovery of the testosterone levels after suppressing by compound IV in rat and monkey
To being studied by the invertibity of compound IV androgen deprivation.
Materials and methods:
35 (35) male Sprague-Dawley rats of great about 200g were maintained under 12 little time/dark cycles, make it arbitrarily obtain food (2016Teklad Global16% protein rodent diet, Harlan, Madison, WI) and water.Animal experiment scheme obtains the care of animal of Tennessee State university and audit and the approval of the committee of use.
Test article for this research are weighed and be dissolved in PEG300 (100%) (Acros Organics, NJ) to prepare suitable dosage particles.By one of animal Random assignment to ten treatment group (n=5 animal/group).In table 7, list treatment group.Animal is raised with the group of 2 to 3 animals of every cage.By the 1st group when research starts (the 1st day) put to death for measuring the baseline testosterone levels of intact animal.The 2nd to 7 groups continue three days via oral every daily dose of raising by force (about 200uL) acceptance 1,3 or 30mg/kg.The 2nd group, the 3rd group and the 4th group are put to death to measure maximum testosterone compacting the 4th day time.Make the 5th group, the 6th group and the 7th group without the medicament elution phase, recovering 14 days.
Table 7. treatment group.
Result:
Under baseline, the level of serum testosterone in intact rats is 6.4 ± 3.1ng/mL (mean value ± S.D).With 3 and the dosage of 30mg/kg continue the compound IV used for three days respectively by level of serum testosterone significantly compacting to 1.47 ± 0.26 and 1.62 ± 0.49ng/mL.In the animal that continues three days in the compound IV of accepting 1mg/kg, do not observe remarkable compacting.Most important ground, when measuring after 14 day convalescence, accept respectively 1,3 or the compound IV of 30mg/kg continue three days animal in level of serum testosterone be 3.3 ± 1.92,3.00 ± 1.06 and 3.8 ± 1.72, and as described in Figure 23, the baseline serum testosterone concentration in described level and intact rats does not have statistically-significant difference.
This studies confirm that previous result, thereby demonstration compound IV is suppressed the level of serum testosterone in complete male rat rapidly.In the dosage group that continues three days in acceptance >=3mg/kg/ days, observe the compacting of level of serum testosterone.1mg/kg dosage group is not observed the remarkable minimizing of serum testosterone.Yet in 14 days recover, level of serum testosterone has been back to the level of complete contrast.This studies show that the pharmacology castration of being undertaken by compound IV is reversible in rat.
In conjunction with oral drugs dynamic metabolism, study assessing compound IV to the compacting of testosterone levels in complete male monkey and the effect of recovery.Three Rhesus Monkeys of not treated (2 to 3 years old age) are raised by force with continuous 7 days of 30mg/kg administered compound IV every day by oral.Collect blood sample and be divided into serum and plasma and be respectively used to testosterone and compound IV quantitative measurment.Compare with baseline values, result show the compound IV of oral dose every day make circulation androgen (being mainly testosterone and dihydrotestosterone) level in all three male monkeys significantly reduce up to 47% (for baseline, treatment the 2nd day and the 6th sky and water divide equally be not 1591 ± 72.5,997 ± 104 and 852 ± 136ng/mL[mean value ± SEM]).At 18 days, without medicine after convalescence, androgen levels was back to normally, and from baseline values before treatment without significantly different (1757.7 ± 369.5ng/mL after recovering).
Embodiment 11
Although reduce LH and testosterone in rat, still preserve sclerotin (table 8)
Studied the effect of formula IV compounds for treating to sclerotin.Orally administered formula IV compound has prevented to suppress relevant bone-loss to the LH in complete male rat completely.In intact animal by induced the remarkable reduction of LH with the formula IV compound of every day >=10mg/kg dosage level.Although the formula IV compound of 1mg/kg/ days does not significantly reduce LH, under this dosage, the remarkable minimizing of prostate, seminal vesicle and musculus levator ani is significantly, thereby the minimizing of indication circulation testosterone is relevant on physiology to these androgen response organs.Yet the formula IV compound of 1mg/kg/ days maintains trabecular bone volume (measuring in distal femoral) level of complete contrast.When using with the dosage of every day 10 and 30mg/kg, formula IV compound makes the bone volume in distal femoral be increased to the bone volume that is significantly higher than complete contrast.Under the dosage level of the LH level of these data demonstration compound IV in reducing intact rats, increase trabecular bone mineral density (BMD) and bone volume percentage.Data from this research are presented in table 8.
Table 8. compound IV is to acting in the body of rat sclerotin, organ weight and serum hormone parameter
acontrast complete medium, P<0.05. bcontrast ORX medium, P<0.05
Embodiment 12
Effect to 17 beta hydroxysteroid dehydrogenase 5 (17 β-HSD5) enzymic activitys
HSD family member relates in the conversion of circulation steroids.17 β-HSD5 changes into androstenedione testosterone and oestrone is changed into estradiol.In addition, it also relates in prostaglandin is synthetic.At this, proved that the compound of selections more of the present invention suppresses the ability of 17 β-HSD5 activity.
Method
People 17 β-HSD5 is cloned in pGEX4t1 carrier and prepares the protein of purifying.By the protein of purifying and representative compound of the present invention, 14c androstenediol and NADPH are hatched in suitable buffer solution.
With ethyl acetate, extract synthetic testosterone, its air is dry, on thin-layer chromatography (TLC) plate point sample and run sample.TLC is exposed to the intensity of Phosphorescence imaging instrument and quantification testosterone bands of a spectrum.Indomethacin (Indomethcin) is as positive control (LHRH activator).
Result
Compound IV is tested and it has partial inhibition to 17 β-HSD5 enzymic activity.As was expected shows the strong inhibitory action to this kind of enzyme for positive control (LHRH activator) Indomethacin, as presented in Fig. 3.
Embodiment 13
Toxicity research
Use vitro human platelet aggregation to measure and study the thrombosis potentiality with comparative compound IV and diethylstilbestrol (DES, positive control).From the blood of healthy male donor for described research because male, be compound IV (LH compacting) be intended to treat colony.To be rich in hematoblastic estradiol (E2) for blood plasma, DES, compound IV or medium preincubate 30 seconds, and then add fibrin ferment (0.3 unit) and assemble with induced platelet.The result of described research shows makes the platelet aggregation of thrombin induction increase about 10 times with DES preincubate.Yet the gathering that compound IV and estradiol make to be rich in hematoblastic blood plasma reduces.These digital proofs are compared with DES, and compound IV has reduced the hematoblastic reactivity of vitro human, and show that compound IV can have the thromboembolism potentiality (Fig. 4) lower than DES.
Embodiment 14
The effect of compound IV to hot flash
Use morphine dependent rat model (MD model) to study to investigate the effect of compound IV to hot flash, described model by (1983) exploitations such as Simpkins and demonstration and climacteric hot flash there are some similitudes.Except the similitude with people's symptom, this experimental animal model has short turnover period, and this makes it become the useful high flux screening instrument that can alleviate the compound of vasomotor symptoms for using Tail skin temperature (TST) to differentiate.TST probe TA-40 (Data Sciences International, MN) is bonded to the basal part of tail, and obtains datum temperature lasting 15 minutes.After 15 minutes, naloxone (1mg/kg, SQ) for animal is treated to reverse to the effect of morphine.After the treatment of nano ketone, continue to measure a Tail skin temperature (TST) in, in whole experimentation, sample frequency is 5 seconds.After data acquisition, the moving average of calculating and the temperature that further dissecting needle records every animal per for 60 seconds.Datum temperature is calculated as the mean temperature of obtaining in 15 minutes before naloxone is used.By carrying out area under calculated curve (AUC) with all values that linear trapezoid method deducts nano ketone is used from baseline.
Compound IV weakens the hot flash (referring to Figure 13) in morphine abstinence syndrome model, under 10mg compound IV, has optimum.In 100%DMSO, with 5mg/kg, use 17 β E2.
Embodiment 15
Compound IV contrast DES in rat
Before introducing LHRH activator, by the estrogen active increasing in hypophysis via oestrogenic hormone (being mainly diethylstilbestrol (DES)), realize castration testosterone levels.DES testosterone is suppressed horizontal to castration aspect with LHRH activator effective equally.With the patient of DES treatment, can not there is hot flash or bone-loss, but really have with using the ADT of LHRH activator, compare, more the gynecomastia of height ratio.Unfortunately, the excessive risk of the cardiovascular and thromboembolic complication that efficient, pure oestrogenic hormone (as DES and estradiol) is frequent and serious is associated, and this has limited their clinical practice.Supposed but proof not, the risk of the increase of the VTE complication of DES is the cross reactivity due to itself and other hormone receptor.The in vitro study of carrying out with human blood platelets shows that compound IV has the procoagulant activity more much lower than DES.Therefore, the prostate cancer benefit that compound IV (a kind of ER-alpha selective activator) can be sent DES, and the benefit of sending LHRH activator, and do not cause osteoporosis or unfavorable lipid feature.
Compound IV the prostate size that reduces rat with present the appropriateness increase of prostate size of ORX rat aspect with DES equally effective (Figure 11).
Difference between DES and compound IV is presented in Figure 12 A to 12C, wherein DES and glucocorticoid receptor (GR) (Figure 12 A) and androgen receptor (AR) (Figure 12 B) cross reaction, and compound IV can not.In addition, the trans-activation of DES antagonism estrogen-related receptor (ERR), compound IV can not.As described in Figure 12 C, compound IV not with three kinds of ERR isoforms (ERR-α, ERR-β and ERR-γ) in any cross reaction.
Embodiment 16
Monkey Du Yan Jiu – 90 days
Obtain the rhesus macaque of the group support type breeding in Mauritius (Mauritius) source.Perspective study is designed to 39 weeks oral medicine Neo-Confucianism and the toxicological evaluation of compound IV and positive control (LHRH activator) in Rhesus Monkey, wherein has the mid-term of 13 weeks.Sexually matured male monkey Random assignment to five group before treatment starts in 39 5 to 8 years old age will be amounted to.Group comprises: 1) medium contrast, 2) 1mg/kg compound IV, 3) 10mg/kg compound IV, 4) 100mg/kg compound IV and 5) positive control (LHRH activator).By cage limit, using once a day oral delivery sustained drug 39 weeks, is wherein medium contrast article (Tween80/PRANG for the 1st group and the 5th group tM), or be the compound IV in medium for the 2nd group, the 3rd group and the 4th group.For the 2nd group, the 3rd group and the 4th group, the dosage level of compound IV is respectively 1,10 and 100mg/kg/ days.Oral dose is to send with 10mL/kg dose volume, and described dose volume is that the nearest obtainable body weight based on every animal is calculated (Figure 14).Animal in the 5th group is also accepted hypodermic positive control (LHRH activator) (0.02mL constant volume) once a day and continues 39 weeks research phases.Observe and record overall appearance and clinical symptom every day.Other research of evaluating and selecting as conventional in carrying out indicated in research approach.The parameter of selecting includes but not limited to, testosterone, prostate specific antigen (PSA) and prostate volume and weight.
Use respectively enzyme immunoassay (EIA) (EIA) method and CLIA (LIA, ALPCO Diagnostics, Salem NH) in blood serum sample, to quantize (according to standardization program) testosterone and t-PSA level.During at baseline (that is, before begin treatment) and the 1st day, the 3rd day, the 7th day, the 14th day, the 28th day, the 64th day and the 90th day, from all animals (under fasting state), collect the blood sample of evaluating for testosterone.At baseline and during the 6th week, from all animals (under fasting state), collect the blood sample of measuring for PSA.For purposes of discussion, the concentration of measuring for testosterone and PSA is calculated as to the quantification lower limit (LLOQ) of mensuration lower than the result that quantizes the sample of limit (BLQ) , and be considered to " ultimate density of estimation ".Except, " ultimate density of estimation " (that is have as measuring lLOQ and the sample of the BLQ result that included) outside, table 9 to the data in 16 are rendered as " only quantifiable concentration " (that is, get rid ofbLQ value).At baseline and the 6th week use TRUS (TRUS) program, under anesthesia, in animal alive, measure prostate volume.Record prostatic width and height.Prostate volume is calculated as width * width * highly * pi/6 and is standardized to body weight.After pruning not fatty tissue and outside organization, record prostatic weight in wet base during in ptomatopsia.
results and discussions:
At Figure 15 and table 9, present level of serum testosterone in to 12.At baseline place, the testosterone levels of all monkeys of studying is all in the normal range (NR) of sexually matured bull rhesus macaque.Yet testosterone levels is in accepting the monkey of compound IV of 100mg/kg/ days and significantly reduce in the monkey with positive control (LHRH activator) treatment.Testosterone levels in positive control (LHRH activator) group illustrates two phase change, wherein initially respectively when the 1st day and the 3rd day significantly increase (, rubescent) 47.4% and 547% (p<0.01) then reduces by 3.6%, 67%, 73%, 83% and 85% (referring to Figure 15 and table 9 to 12) when the 7th day, the 14th day, the 28th day, the 64th day and the 90th day.For any animal with compound IV treatment, even under maximum dose level level (that is, 100mg/kg/ days), also do not observe similarly rubescent.Dosage and treatment duration, the pharmacology of compound IV is done was important, and wherein the dosage of 100mg/kg/ days reaches 60%, 51%, 42%, 79% and 92% (referring to Figure 15 and table 9 and 10) with respect to baseline value compacting serum testosterone respectively when the 3rd day, the 7th day, the 14th day, the 28th day and the 64th day.After with compound IV treatment in 100mg/kg/ days 90 days, 6 testosterone levels of merely hitting in the 4th group of 10 monkeys are reduced to the concentration (referring to table 11) lower than the quantification limit of measuring.Compare with corresponding baseline value (" ultimate density of estimation ", that is, the testosterone levels with 6/10 monkey of BLQ value is calculated as 50% of LLOQ concentration, referring to table 10), the average serum testosterone levels in the 4th group of monkey is lowered 96%.Importantly be noted that the 90th day, with the compound IV of 100mg/kg/ days, serum testosterone be reduced to significantly to the level (p=0.013) lower than positive control (LHRH activator).
Table 9. is the average serum testosterone levels (ng/mL) in complete male monkey after every day Orally administered compound IV; The ultimate density that@estimates.
Testosterone is measured LLOQ=0.246ng/mL; @BLOQ value is calculated as 0.123ng/mL, half of LLOQ.
*: the contrast of compound IV 100mg/kg contrast medium, statistically remarkable (p<0.05)
#: the contrast of positive control (LHRH activator) contrast medium, statistically remarkable (p<0.05)
$: positive control (LHRH activator) control compounds IV100mg/kg, statistically remarkable (p<0.05)
Table 10. is compared with baseline, the variation percentage (%) of average serum testosterone levels; The ultimate density that@estimates.
Testosterone is measured LLOQ=0.246ng/mL; @BLQ value is calculated as 0.123ng/mL, half of LLOQ.
Table 11. is the average serum testosterone levels (ng/mL) in complete male monkey after every day Orally administered compound IV; λquantifiable concentration only
Testosterone is measured LLOQ=0.246ng/mL; λget rid of BLQ value.
Table 12. is compared with baseline, the variation percentage (%) of average testosterone levels; λquantifiable concentration only.
Testosterone is measured LLOQ=0.246ng/mL; λbLQ value is excluded.
In the surrounding starting in treatment, Serum PSA level is combined thing IV compacting significantly also.The monkey that continues 4 weeks for the compound IV of accepting 10mg/kg and 100mg/kg, notice that 69% and 87% PSA reduces (mean value), and PSA level is lowered 60% (Figure 16 and table 13 are to 16) in positive control (LHRH activator) group.
Table 13. is the average serum PSA level (ng/mL) in complete male monkey after every day Orally administered compound IV; The ultimate density that@estimates.
PSA measures LLOQ=0.0575ng/mL; @BLQ value is calculated as 0.02875ng/mL, half of LLOQ.
*: the contrast of compound IV 10mg/kg contrast medium, statistically remarkable (p<0.05)
The contrast of &: compound IV 100mg/kg contrast medium, statistically remarkable (p<0.05)
#: the contrast of positive control (LHRH activator) contrast medium, statistically remarkable (p<0.05)
$: positive control (LHRH activator) control compounds IV100mg/kg, statistically remarkable (p<0.05)
Table 14. is compared with baseline, the variation percentage (%) of mean P SA level; The ultimate density that@estimates.
PSA measures LLOQ=0.0575ng/mL; @BLQ value is calculated as 0.02875ng/mL, half of LLOQ.
Table 15. is the average serum PSA level (ng/mL) in complete male monkey after every day Orally administered compound IV; λquantifiable concentration only.
PSA measures LLOQ=0.0575n g/ mL; λbLQ value is excluded in this table.
Table 16. is compared with baseline, the variation percentage (%) of mean P SA level; λquantifiable concentration only.
PSA measures LLOQ=0.0575ng/mL; λbLQ value is excluded in this table.
In whole research, by TRUS, periodically measure prostate volume.The result proof compound IV obtaining after treatment in six weeks and positive control (LHRH activator) are to the prostatic useful effect of monkey.Under 10mg/kg and 100mg/kg dosage level, compound IV is suppressed significantly respectively prostate volume and is reached 25% and 45%, and prostate volume is reduced 28% (Figure 17 and table 17 and 18) in positive control (LHRH activator) group.
Table 17. is the average prostate volume (ratio) in male monkey after every day Orally administered compound IV.
Table 18. is compared with baseline, the variation percentage (%) of average prostate volume.
The minimizing relevant to compound IV of prostate volume aspect confirmed by the evaluation of weight of prostate when the ptomatopsia.After treatment 13 weeks, accept 10 and the animal of 100mg/kg/ days in, compound IV makes respectively average weight of prostate reduce by 24% and 21% (Figure 18 B and table 19 and 20) significantly.
Table 19. when ptomatopsia every day Orally administered compound IV monkey in average weight of prostate (gram)
Table 20. is compared with baseline, the variation percentage (%) of average weight of prostate.
Do not observe the obvious effect to the partial thromboplastin time (APTT) of platelet aggregation, prothrombin time (PT) or activation.
Embodiment 17
Compound IV research for people
Study to determine the effect of compound IV to human male.With 100,300,600 and the dosage of 1000mg compound IV check 12 experimenters of every cohort.Table 21 presents by with 100,300,600 and the dosage administered compound IV of 1000mg, the mean change of LH, blood-serum P SA, free testosterone level and total testosterone levels in the male sex.The average total testosterone levels (nmol/L) of dose dependent in a period of time measurement human body between lasting 1 to 11 day (Figure 19).Under the dosage of 600mg and 1000mg, total testosterone levels reduces respectively 51.9% and 47.9%.
The average LH level of dose dependent (IU/L) in a period of time measurement human body between lasting 1 to 10 day (Figure 20).Under the dosage of 100mg, 300mg, 600mg and 1000mg, LH level increases respectively 20.7%, 46.9%, 27.6% and 29.2%.
The average free testosterone level of dose dependent (pg/mL) in a period of time measurement human body between lasting 1 to 10 day (Figure 21).Under the dosage of 100mg, 300mg, 600mg and 1000mg, free testosterone level reduces respectively 17.0%, 18.5%, 72.7% and 53.2%.
Dose dependent mean P SA level (μ g/L) in a period of time measurement human body between lasting 1 to 10 day (Figure 22).Under the dosage of 100mg, 300mg, 600mg and 1000mg, PSA level reduces respectively 9.2%, 24.4%, 27.5% and 29.9%.For 10 and 30mg dosage do not notice variation.
Table 21. is from the mean change of baseline.
? 100mg 300mg 600mg 1000mg
Blood-serum P SA -9.2％ -24.4％ -27.5％ -29.9％
LH 20.7％ 46.9％ 27.6％ 29.2％
Free testosterone -17.0％ -18.5％ -72.7％ -53.2％
Total testosterone 3.9％ 7.3％ -51.9％ -47.9％
These data are presented at testosterone and PSA decline under the background rising at LH in the early stage time point process in this people's test.This supports via suppressing different mechanism compacting testosterones and corresponding anti-androgenic effect (PSA compacting) from thalamus-hypophysis-testis axis.For the mechanism of this LH independence compacting, can be especially compound IV to suprarenal gland or the synthetic direct effect of sexual gland androgen or due to the chelating of the serum T due to the rising of SHBG.
Embodiment 18
The biological usability of compound IV
After being administered orally to rat, dog and monkey, compound IV is absorbed rapidly.In rat, the oral biological usability of compound IV is in 6% to 25% scope, and this depends on the preparation at institute's application dosage.Use the preparation of Liquid Macrogol (PEG300) conventionally to produce the higher exposure of microemulsion than preparation is diluted in deionized water in Tween80.In dog, the visual inspection of plasma concentration-time graph shows, the recycle of compound IV experience intestines liver, as the second peak value in latter stage proves.Importantly, in dog, the exposure in male 30mg/kgPEG300 oral dose group is in the rat model of LH compacting, prostate being reduced and produces the required exposure of maximum effect.In monkey, tentatively pharmacokinetics research shows, the oral biological usability in this species approaches or surpasses the oral biological usability in dog, as proved by the plasma concentration of compound IV and the obsession of serum testosterone within seven day period.Generally speaking, these data show in two kinds of non-rodent species, to realize enough oral required pharmacotoxicological effects (based on AUC data) that is exposed to produce.In addition, the internal secretion data in rat and monkey show, the pharmacotoxicological effect of compound IV is reversible (that is,, when stopping treating by compound IV, the serum-concentration of testosterone is back to baseline or normal level).
Therefore,, after being administered orally to rat, dog and monkey, compound IV is absorbed rapidly.The oral biological usability of compound IV in rat in 6% to 25% scope, and in dog in 3% to 12% scope, this depends on preparation and route of administration.In monkey, tentatively pharmacokinetics research shows, the oral biological usability in this species approaches or surpasses the oral biological usability in dog, as the obsession of the plasma concentration by compound IV and serum testosterone proves.In addition, the internal secretion data indication in rat and monkey (embodiment 10), the pharmacotoxicological effect of compound IV is reversible, wherein, when stopping treating by compound IV, serum testosterone concentration is back to baseline or normal level.
Embodiment 19
The pharmacokinetics of compound IV
The conjugate, its one or more hydroxylated metabolite that shows compound IV from (rat) metabolism research in the preliminary data of external (mouse, rat, dog, monkey and people) and body with and the metabolite of N-dealkylation total place of compound IV in animal and human is equipped with to impact.The result comparing between species, although be only qualitatively, shows that the overall metabolite curve of non-clinical species reflects the curve producing in people's hepatomicrosome fully.Based on these results, rat and dog are respectively for the suitable rodent of pharmacology and toxicological evaluation and non-rodent species.In vitro study demonstration compound IV can not induced relevant CYP450 isoform (CYP1A2, CYP2B6 or CYP3A4) and can not suppress CYP1A2, CYP2C19, CYP2D6 or CYP3A4/5 under concentration <30 μ M.The combined thing IV of CYP2C9 suppresses, but this is only at high concentration (K i=8 μ M) under, and potential pharmacokinetics drug-drug interactions is considered to far away.
Embodiment 20
The activity of missing the target of compound IV
Compound IV applies very little or there is no an In-vitro Inhibitory Effect (IC hERG passage 50>=300 μ M).Described compound 10 with under the concentration of 100 μ M, reduce in vitro APD50 and APD90 in separated dog Purkinje fiber dose dependent.Yet compound IV does not affect Hemodynamics in the dog of remote measurement or cardiac function (blood pressure, heart rate, electrocardiogram form or QT interval) under any dosage (up to 300mg/kg).Do not observe Neuropharmacology or lung effect.In the situation that up to the single oral dose of 30mg/kg compound IV, do not notice the remarkable effect to renal function.Under tested maximum dose level (100mg/kg), only observe the output of urine volume and potassium and the muriatic homaluria of increase.Oral dose administered compound IV with 30 to 300mg/kg in rat produces the remarkable increase of wriggling, and the remarkable increase (can not be due to the effect to smooth muscle) that produces gastrointestinal motility and gastric acidity with the Orally administered compound IV of 30mg/kg in rat.
Compound IV is not mutagenic, and can be not external under the concentration up to 200 μ M in human peripheral lymphocyte inducement structure or number heterosomal aberration.Single and Orally administered (reaching 28 days) that repeat afterwards, compound IV is well tolerable by rat and dog.In the relevant organ of kidney, liver, heart and other non-target, do not observe pathological change.Do not exist to Orally administered compound IV to male or female dog and last up to relevant serious physical signs, body weight effect, clinical pathological change, eye, electrocardiogram or histopathology variation in 28 days.
Embodiment 21
Compound IV makes testosterone be reduced to castration level
In healthy young men volunteer, carry out Proof of Concept researchs in 56 days of compound IV.In the experimenter who fully complys with aspect taking compound IV, as the blood level by compound IV, measured, be studies show that in 1500mg dosage group 90% experimenter to the reaches the castration level of total testosterone for 28 days.Free testosterone level is reduced to lower than from the desired level of operation castration or from the level by LHRH activator or the desired level of antagonist androgen deprivation.This is owing to using the dose dependent of the viewed sex hormone binding globulin of compound IV (SHBG) to increase.SHBG is closely in conjunction with testosterone, thereby make intracellular reactive unavailable, and the level that increases SHBG reduces the testosterone that is available for working in cell, thereby the pharmacology benefit of compound IV is provided potentially, and described benefit does not exist in operation castration or by LHRH activator or antagonist castration in the situation that.
The experimenter that serum levels based on compound IV is fully comply with in variation percentage % from baseline to final observed result
in this analysis, included experimenter is the experimenter who there is no EDC (except castration) and can not confirm non-compliance.
* 2 experimenters reach castration, and then depart from, this may be due to as by the determined compliance to drugs of compound IV level, reduce.
* * 1 experimenter reaches castration, and then departs from.
The experimenter of castration
? 1000mg 1500mg
Castration experimenter's # 9* 11**
Total testosterone -94.7±0.228％ -92.8±0.65％
P-value <0.000000001 <0.000000001
Free testosterone -98.2±0.146％ -97.7±0.155％
P-value <0.000000001 <0.000000001
Blood-serum P SA -52±28％ -43±24％
P-value 0.0523 0.001
FSH -91±5.2％ -88±4.8％
P-value 0.00167 0.000006
SHBG 471±102％ 524±212％
P-value 0.0000002 <0.0000000001
BSAP 6.0±29％ -19±21％
P-value 0.862 0.1475
Osteocalcin -20±15％ -23±17％
P-value 0.0663 0.1228
in this analysis, included experimenter is the experimenter who there is no EDC (except castration) and can not confirm non-compliance.
* 2 experimenters reach castration, and then depart from, this may be due to as by the determined compliance to drugs of compound IV level, reduce.
* * 1 experimenter reaches castration, and then departs from.
Embodiment 22
For the compound IV Yan Jiu – of the monkey of castration 90 days
Obtain the rhesus macaque of the group support type breeding in Mauritius source.Perspective study is designed to 39 week oral medicine Neo-Confucianism and the toxicological evaluation of compound IV in Rhesus Monkey, wherein has the mid-term of 13 weeks, thereby the animal of castration and non-castrated animal are compared to (embodiment 16).Sexually matured male monkey Random assignment to 7 group before treatment starts in 49 5 to 8 years old age will be amounted to.To select the animal for the 3rd to 7 groups to carry out castration according to NIH guide.Group comprises: 1) complete medium contrast, 2) complete positive control (LHRH activator), 3) medium of castration contrast, 4) the 1mg/kg compound IV of castration, 5) the 10mg/kg compound IV of castration, 6) the 100mg/kg compound IV and 7 of the castration) contrast (LHRH activator) of castration.
By cage limit, using once a day oral delivery sustained drug 39 weeks, is wherein medium contrast article (Tween80/PRANG for the 1st group, the 2nd group, the 3rd group and the 7th group tM), or be the compound IV in medium for the 4th group, the 5th group and the 6th group.For the 4th group, the 5th group and the 6th group, the dosage level of compound IV is respectively 1,10 and 100mg/kg/ days.Oral dose is to send with 10mL/kg dose volume, and described dose volume is to calculate as the nearest obtainable body weight based on every animal.Animal in the 2nd group and the 7th group is also accepted hypodermic LHRH activator (0.02mL constant volume) once a day and continues 39 weeks research phases.Observe and record overall appearance and clinical symptom every day.Other research of evaluating and selecting as conventional in carrying out indicated in research approach.The parameter of selecting includes but not limited to, testosterone, prostate specific antigen (PSA) and prostate volume and weight.
Use respectively enzyme immunoassay (EIA) (EIA) method and CLIA (LIA, ALPCO Diagnostics, Salem NH) in blood serum sample, to quantize (according to standardization program) testosterone and t-PSA level.During at baseline (that is, before begin treatment) and the 1st day, the 3rd day, the 7th day, the 14th day, the 28th day, the 64th day and the 90th day, from all animals (under fasting state), collect the blood sample of evaluating for testosterone.At baseline place and during the 6th week, from all animals (under fasting state), collect the blood sample of measuring for PSA.For purposes of discussion, the concentration of measuring for testosterone and PSA is calculated as to the quantification lower limit (LLOQ) of mensuration lower than the result that quantizes the sample of limit (BLQ) , and be considered to " ultimate density of estimation ".At baseline place and the 6th week use TRUS (TRUS) program, under anesthesia, in animal alive, measure prostate volume.Record prostatic width and height.Prostate volume is calculated as width * width * highly * pi/6 and is standardized to body weight.After pruning not fatty tissue and outside organization, record prostatic weight in wet base during in ptomatopsia.
Results and discussions:
At baseline place, the testosterone levels of all monkeys in the 1st group and the 2nd group of research is in the normal range (NR) of sexually matured bull rhesus macaque.Yet at baseline place, the testosterone levels of all monkeys in the 3rd to 7 groups of research is reduced to the castration scope of sexually matured bull rhesus macaque.Result is presented at positive controls and accepts testosterone levels in 2 monkeys of LHRH activator and be significantly reduced.Testosterone levels in this complete positive control (LHRH activator) group shows two phase change.Animal for any castration with compound IV treatment does not observe similarly rubescent.It is important that dosage and treatment duration are done the pharmacology of compound IV.
Unexpectedly, in treatment starts surrounding, in the animal (the 4th group, the 5th group and the 6th group) of castration, the combined thing IV of Serum PSA level significantly suppresses.
In whole research, by TRUS, periodically measure prostate volume.Minimum change before complete medium contrast is presented at administration and between 4 weeks.Result proof compound IV is to the prostatic useful effect of monkey.
The similar result of viewed result in complete medium contrast demonstration and embodiment 16.In minimizing relevant to compound IV aspect prostate volume evaluation of weight of prostate when in ptomatopsia, confirm.After treatment in 13 weeks, compound IV significantly reduces the average weight of prostate in the animal of the compound IV of accepting a plurality of dosage.
Do not observe the obvious effect to the partial thromboplastin time (APTT) of platelet aggregation, prothrombin time (PT) or activation.
Embodiment 23
For the compound IV research of carrying out the people who suffers from prostate cancer of ADT
Study to determine that compound IV is to carrying out for the testosterone in the human male of the ADT of prostate cancer and the effect of PSA level, wherein ADT treatment causes experimenter to have castration testosterone levels.All experimenters are required to illustrate the Histological Evidence of prostate cancer.Not yet carry out previous orchiectomy and accepting at present LHRH analog being required to keep carrying out this therapy at research process for the patient of androgen deprivation.
With 100,300,600 and the dosage of 1000mg compound IV check 12 experimenters of every cohort.Measure the average total testosterone levels (nmol/L) of dose dependent in human body one period between lasting 1 to 11 day.
Measure the average free testosterone level of dose dependent (pg/mL) in human body one period between lasting 1 to 10 day.
Measure the dose dependent mean P SA level (μ g/L) in human body one period between lasting 1 to 10 day.
Embodiment 24
Compound IV research for normal volunteer
Compound IV toxicity research in normal volunteer
Single and multiple dose in normal volunteer studies show that compound IV the single dose up to 1247mg and last up to 10 days until under up to the multiple dose of 997mg (10,30,100,300,609 and 997mg) by well tolerable.In four experimenters in multiple dose research (3 experimenters in 1000mg group and 1 experimenter in 600mg group), there is the observed result higher than the ALT level of the rising of upper limits of normal.The highest single observed value of ALT is 129IU/L or upper limits of normal 2.6 times.In this experimenter, aspartate transaminase level is also increased to 1.9 times of upper limits of normal.In any experimenter in described test, all not observing total bilirubin raises.
The effect of compound IV to level of serum testosterone
In whole multiple dose research, evaluate the total testosterone levels of serum.In the experimenter of total testosterone levels in 100% (10/10) 600mg dosage group, in reduction and the experimenter in 90% (9/10) 997mg dosage group, reduce.In the experimenter of the level of total testosterone in 40% (4/10) 600mg dosage group, be reduced to lower than being reduced to lower than normal lower limit in normal lower limit and the experimenter in 50% (5/10) 1000mg dosage group.Yet, do not have experimenter to there is the total testosterone levels lower than 1.73nmol/L (castration scope), and be back to normally in after ending compound IV 6 days of total testosterone levels of all experimenters.
For evaluating compound IV, to the Proof of Concept research (research 1) of the effect of the total testosterone of the serum of the young male volunteers of health and free testosterone, (wherein healthy male volunteers is taken 600mg, the compound IV that is solution form of 1000mg or 1500mg continues 56 days) be presented at 1000 and 1500mg dosage group in, some experimenters have the total testosterone levels of serum of within the scope of castration (<1.73nmol/L), and in 600mg dosage group, do not have experimenter to there is the total testosterone levels of serum of within the scope of castration (<1.73nmol/L).
Also carried out the second Proof of Concept research (research 4) to evaluate compound IV to the total testosterone levels of serum in the older male volunteers of health and the effect of free testosterone level.In this research, the compound IV that is tablet form that volunteer takes 1000mg, 1500mg or 2000mg continuously continues 28 days.
In these two researchs, compound IV shows that the dose dependent of sex hormone binding globulin (SHBG) increases.SHBG is bonded to testosterone, thereby produces disabled conjugate for being bonded to androgen receptor, and reduces the level (as indicated by the level of free testosterone) of available testosterone for being bonded to androgen receptor.In each dosage group of using in these two researchs, SHBG has increased 300%-600% than baseline, and free serum testosterone reduces.In the male sex of the androgen deprivation of total testosterone levels <50ng/dL, the level expection of free serum testosterone lower than with operation castration with use the desired level of luteinising hormone-releasing hormo (LHRH) activator.
The summary of different human research's details is presented in Figure 26.
Embodiment 25
For the compound IV research of suffering from the male subject of prostate cancer:
Compound IV is to the Zuo of level of serum testosterone – patients with prostate cancer
Carried out Investigation on Dose research (research 2), 1000mg and the 2000mg compound IV dosage of using once a day together with three months depot formulations with leuprorelin acetate has been compared in described research.The main purpose of described research is that evaluation reached the total testosterone of serum of castration level and from the 60th day to the 360th day, maintaining the experimenter's of castration level ratio by the 60th day.
By 55 (55) experimenter's Random assignments to 1000mg compound IV dosage group.In 1000mg compound IV dosage group, in reaching the experimenter of the 60th day, 65% (24/37) experimenter to the realizes castration in the time of 60 days.Yet as androgen-deprivation monotherapy, this ratio of experimenter of reaching castration is too low and can not be considered to feasible clinically.
By 55 (55) experimenter's Random assignments to 2000mg compound IV dosage group.In 2000mg dosage group, reaching among the experimenter of the 60th day, 84% (38/45) experimenter to the realizes castration in the time of 60 days.
By 54 (54) experimenter's Random assignments to leuprorelin acetate dosage group.In the group of effect of leuprolide, reaching among the experimenter of the 60th day, these experimenters to the of 100% (46/46) realize castration in the time of 60 days.In described research process, nine (9) experimenters in 1000mg dosage group and two (2) experimenters in 2000mg dosage group experience VTE.
The second object of research 2 is the incidence of disease and frequencies that the experimenter of comparison administered compound IV contrasts hot flash in the experimenter who uses Leuprorelin (Lupron).According to the show, compare with the male sex who uses Leuprorelin, the male sex of administered compound IV experiences less hot flash.
Following table presents the result of using injectable LHRH activator (Leuprorelin) to contrast the incidence of disease of hot flash in the male sex that oral selective estrogen receptor alfa agonists (compound IV) carries out androgen-deprivation therapy.:
Carried out another research (research 5) with evaluate every day twice 1000mg and every day twice 1500mg load doses compound IV continue 28 days.In the time of the 28th day the experimenter of castration accept every day 1000mg or 2000mg compound IV to maintain castration.
30 (30) and 28 experimenters are distinguished to Random assignment to 1500mg BID and 1000mg BID load doses.Reaching among the experimenter of the 28th day, 94% (17/18) experimenter in 90% (18/20) experimenter in 1500mg BID dosage group and 1000mg BID dosage group has reached the castration level of the total testosterone of serum.In this research, two (2) experimenters in 1500mg BID dosage group experience VTE (comprising a routine mortality pulmonary embolism (PE)), and three (3) experimenters in 1000mg BID dosage group experience VTE.
The summary of research details is presented in Figure 26.
Table 22. is accepted the castration rate of the patients with prostate cancer of not treated of >14 days compound IV.
In the patient who had not treated, when checking free T% from the variation of baseline, 81% T% that dissociates after treatment in 7 days is only reduced by least 50% (Figure 28 A).When treatment extends to 14,21 and 28 days, this variation of free T% is associated with the minimizing of PSA.After the compound IV treatment of month (Figure 28 D), in all patients, there is 80% free T% from baseline, to reduce by 50% (that is the data of, trooping in left lower quadrant in Figure 28 C) from baseline reduction at least 50% and PSA.These patients meet the PCWG2 standard of PSA reaction.
During using the 28th day, the reduction of 50% free T and 50%PSA is plotted in Figure 29 again as the variation of the variation contrast PSA of SHBG.The >50% that the SHBG induction of broad range can realize PSA reduces.
In the patient who had not treated, after treatment in 28 days, compound IV and effect of leuprolide all increase SHBG significantly: the mol ratio (Figure 31) of total T.Because compound IV is induced SHBG and reduces total T, SHBG is high 3 to 7 times with the patient of the mol ratio effect of leuprolide of total T.The mol ratio of this increase is corresponding to 70% of free T% declining the 28th day time in the patient of compound IV treatment, this with the male sex of effect of leuprolide in only 20% reduce to form and contrast (Figure 31).In addition, the compound IV of all dosage shows similarly reducing fast of free T%, thus show 1000mg QD be Emax dosage and more the compound IV of low dosage likely reduce free T%.
Based on clinical experience, from the SHBG data of studying 1 and 2, be extrapolated to compared with low dosage (Figure 32), thereby even if show under 125mg, 250mg and 500mg dosage, SHBG also can be raised to is enough to suppress significantly free T% and PSA.
Embodiment 26
For the compound IV research of carrying out the male subject of suffering from castration resistance prostate cancer (CRPC) of ADT:
The effect of compound IV to blood-serum P SA progress
When measuring total testosterone, described measurement comprises the testosterone of testosterone, free testosterone and the albumin combination of SHBG combination.SHBG is closely in conjunction with testosterone, and the testosterone of while free testosterone and albumin combination is in poised state.Compound IV has shown to be increased SHBG and free testosterone is reduced to the level lower than the level realizing by LHRH activator or antagonist or operation castration.
Be studied (research 3) to evaluate compound IV to suffering from the effect of the blood-serum P SA progress in the male sex of castration resistance prostate cancer, the described male sex has carried out treatment effectively and has shown blood-serum P SA progress recruiting in this research with ADT.This research is comprised of a dosage group with 9 experimenters.
The summary of research details is presented in Figure 26.
The object of this research is: (a) evaluation compound IV is to maintaining the effect (blood-serum P SA reaction and blood-serum P SA progress) of the Serum PSA level in the male sex who suffers from castration resistance prostate cancer who carries out androgen-deprivation therapy; (b) effect of evaluation compound IV to free serum testosterone levels; (c) effect of evaluation compound IV to SHBG; (d) effect of evaluation compound IV to the total testosterone of serum; (e) effect of the development that evaluation compound IV shifts new bone; (f) effect (internal organ and lymph node) that evaluation compound IV shifts soft tissue; And safety and the tolerance of (g) evaluating compound IV in the male sex who suffers from prostate cancer who carries out androgen-deprivation therapy.
Experimenter is 12 18 years old above male subject suffering from castration resistance prostate cancer, described experimenter is using androgen-deprivation therapy (chemistry or operation castration) to treat to continue at least 6 months, when research is recruited, blood-serum P SA>2ng/mL, or >2ng/mL and have 25% increase higher than starting androgen-deprivation therapy (ADT) minimum afterwards.Described experimenter maintains and carries out androgen-deprivation therapy in whole research.
In order to meet the definition of castration resistance, experimenter is necessary: (1) has the blood-serum P SA in can not detection range at two consecutive hours pointers, and then blood-serum P SA rises to >2ng/ml, carries out suitable androgen-deprivation therapy simultaneously; (2) there is the total testosterone of serum (<50ng/dL) of castration level; (3) after starting ADT, there is the history of blood-serum P SA reaction, and (blood-serum P SA react be blood-serum P SA be reduced by least 90% to <10ng/mL or blood-serum P SA can not detection level (<0.2ng/mL)); (4) when twice continuous evaluation of at least two weekly intervals, there is the blood-serum P SA of rising, and Serum PSA level >2ng/mL, or >2ng/mL and higher than having 25% increase starting androgen-deprivation therapy (ADT) minimum afterwards; And (5) proceed androgen-deprivation therapy in whole research.
Table 23. is respectively from research 1; 2 and 5; And the baseline hormone parameter of 3 young health volunteer, older patients with prostate cancer of not treated and castration resistance patients with prostate cancer.
* research 1 adopts the free T method of RIA, thereby when comparing with the preferred dialysis process using in research 2,5 and 3, the free T level that report reduces.
For the selected dosage of described research, it is 2000mg compound IV.Every day Orally administered four tablets of compound IV tablets, 500mg (2000mg dosage).This dosage has shown to be increased SHBG and causes than the remarkable minimizing of free testosterone faster of 1000mg dosage.Experimenter's per os every day is accepted the compound IV of 2000mg until research termination.Continue medication until their blood-serum P SA is starting with twice continuous sampling time after compound IV treatment (approximately interval is 30 days) from minimum increase at least 25% and 2ng/mL.Use PSA progress the definition of prostate cancer working group (blood-serum P SA after starting with compound IV treatment twice continuous sampling during the time from minimum increase at least 25% and than the high 2ng/mL of minimum).
During at baseline and the 15th day, the 30th day and the 60th day, carry out the evaluation (only 1 patient carried out this evaluation before research stops) of blood-serum P SA concentration.
For any experimenter, before observing PSA progress, stop research.Yet, if continue research, will follow following scheme so: after experimenter shows blood-serum P SA progress, experimenter keeps drug administration to continue 30 days and has the blood-serum P of following up a case by regular visits to SA evaluation.If blood-serum P SA progress unconfirmed when making a house call specifically, experimenter keeps under study for action and continuation compound IV administration so.If make a house call middle confirmation blood-serum P SA progress specifically, experimenter gives up the study of and studies and finishes to make a house call evaluation so.Experimenter's arrangement is followed up a case by regular visits to make a house call and is carried out for 30 days after the final dose of compound IV.
Main terminal: blood-serum P SA is from the experimenter's of baseline decline 50% ratio (the 2nd PSA by least one Zhou Yihou evaluates to confirm).
Secondary endpoints: (1) reaches the time of blood-serum P SA progress; (2) blood-serum P SA is from the experimenter's of baseline decline >=90% ratio; (3) variation of free serum testosterone levels; (4) variation of SHBG level; (5) variation of the total testosterone levels of serum; (6) RECIST standard is from the variation of baseline; (7) there is the experimenter's of new bone transfer ratio; (8) there is the ratio that soft tissue new or that worsen shifts the experimenter of (internal organ and lymph node); (9) safety and the tolerance of evaluation compound IV in carrying out the male sex who suffers from prostate cancer of androgen-deprivation therapy.
Medicine is supplied with and preparation: compound IV tablet, the 500mg intensity tablet of preparing together with 1%w/wSDS with micronized drug substance.
In visible Figure 33 of flow chart of descriptive study program.
Result
Described test is by premature termination, but in 12 experimenters that recruit in this research, seven experimenters study long enough to having valuable efficacy data.All seven experimenters show the minimizing of blood-serum P SA on the 15th day from base line system.In being exposed to compound IV all three experimenters of at least 30 days, the >50% that observes blood-serum P SA reduces (Figure 24).
If continue research, will follow following scheme so: accept the blood-serum P SA reactivity that maintaining of compound IV carry out in the male sex who suffers from castration resistance prostate cancer of androgen-deprivation therapy and be the main result of research and evaluate for all experimenters.PSA reaction is defined as declining from 50% of baseline by the 2nd later PSA value confirmation in 4 ± weeks.Estimate the ratio of the experimenter with PSA reaction and calculate accurate 95%Blyth-Still-Casella confidence interval.Among the experimenter of ITT colony, build this estimation.The experimenter who reduces >90% from baseline for PSA carries out this estimation similarly.The diagram of the variation percentage of PSA is described to be presented in Figure 24 via waterfull Curve figure.
Compound IV is to the relation between the effect of SHBG level and SHBG level and free testosterone percentage
In the patient who had not treated from research 2 and research 5 tests, after compound IV treatment in 28 days, baseline SHBG is induced about 150%-700% (Figure 27 A).The reduction strong correlation of SHBG induction and the T% that dissociates [free T (pg/mL)/total T (pg/mL) * 100].The recurrence of relation shows that approximately 400% induction of SHBG reduces and is associated with approximately 75% of free T%.A large amount of patients that do not treated are gathered in this scope, across all dosage of compound IV.Importantly, even when only the compound IV treatment of 15 days is checked, this strong relation also maintains from the CRPC patient who carries out synchronous ADT of research 3 (Figure 27 B).The symbol of opening represents baseline (BL) and closed compound IV treatment as described above for symbol.
Compound IV is to the relation between the effect of free testosterone percentage (free T%) and PSA level and free testosterone percentage (free T%)
The same with the patient who had not treated, the CRPC patient who takes compound IV show free T% fast, be greater than 50% minimizing (the 15th day) (Figure 30).This is with after the compound IV treatment of two weeks only, 3 (closed data point) in 7 patients and 2 (data points of opening) in 3 patients 30 days after middle PSA to be greater than 50% minimizing corresponding.
Experimenter's stopping rule: when starting with after compound IV treatment, the blood-serum P SA in experimenter is from minimum increase 2ng/mL and 25% time at least, and experimenter keeps studying.After 30 days, obtain and follow up a case by regular visits to blood-serum P SA.If described in follow up a case by regular visits to evaluation blood-serum P SA unconfirmed progress, experimenter keeps studying and continues to use compound IV administration so.If described in follow up a case by regular visits to blood-serum P SA progress and confirm blood-serum P SA progress, experimenter gives up the study of and study end and makes a house call and follow up a case by regular visits to and make a house call so.
Blood-serum P SA progress: blood-serum P SA progress will be by PCWG2 standard definition.PCWG2 standard need to be confirmed doubtful PSA progress for 3 to 4 weeks after the PSA level of the possible progress of indication in evaluation.For situation about confirming, PSA makes progress the required time and starts to the time on the date of a PSA level of the possible progress of indication from drugs being.Dead patient will be considered to for the failure of PSA progresson free survival at the trial.The patient's who had not made progress (patient who checked) time starts until their time of finally following up a case by regular visits to the date from drugs being.Blue Meyer (Kaplan-Meier) method of Kapp is by different time point estimation PSA progresson free survival and 95% relevant confidence interval.If realize intermediate value, the intermediate value estimated value of PSA progresson free survival will be estimated so.
Blood-serum P SA progress (PCWG2 definition): if blood-serum P SA initially declines from baseline, so when blood-serum P SA has 25% or larger increase and 2ng/ml or more absolute value while increasing from minimum, as the date that progress occurs, but should confirm by the second blood-serum P SA value obtaining after 3 or more weeks.If there is no blood-serum P SA from the decline of baseline, so when blood-serum P SA had 25% or larger increase and 2ng/ml or more absolute value while increasing after 12 weeks, as the date that progress occurs, but should confirm by the second blood-serum P SA value obtaining after 3 or more weeks.
Other blood-serum P SA analyzes
1. the variation percentage of the time point from baseline to each measurement
2. at the maximum of any time of research decline (the variation percentage from baseline to minimum)
3. the duration of reacting (measuring during thering is the number of days reducing from baseline at least 50%)
Free testosterone: the variation of the free testosterone level while evaluating from baseline to the 15 days, the 30th day, the 90th day and research end.
Total testosterone: the variation of the total testosterone levels while evaluating from baseline to the 15 days, the 30th day, the 90th day and research end.
SHBG: the variation of the SHBG while evaluating from baseline to the 15 days, the 30th day, the 90th day and research end.
Embodiment 27
Compound IV is as the secondary hormonotherapy for metastatic castration resistance prostate cancer (mCRPC)
For the indication secondary hormonotherapy proposing for metastatic castration resistance prostate cancer (mCRPC), compound IV is studied to (research 6).
Compound IV has shown to be increased serum SHBG and free serum testosterone is reduced to the level lower than the level of having observed by LHRH activator or antagonist or operation castration.Compare with leuprorelin acetate treatment group, compound IV group has shown the incidence of disease that has the Bone turnover marker reducing from baseline and have lower hot flash adverse events during suffering from the male sex of advanced prostate cancer.
Studied compound IV as secondary hormonotherapy to maintaining Serum PSA level in the male sex who suffers from metastatic castration resistance prostate cancer of androgen-deprivation therapy and the effect of free serum testosterone levels.The effect that this research evaluation compound IV is made progress to carry out blood-serum P SA reaction in the male sex who suffers from mCRPC of ADT and blood-serum P SA with LHRH activator, lhrh antagonist or orchiectomy.This research also evaluate compound IV compared with the VTE risk of low dosage.Secondary endpoints comprises that free serum testosterone levels, adrenal androgen precursor produce (DHEA and DHEAS level), progresson free survival and bone dependent event (SRE).
The summary of research details is presented in Figure 25.
Research purpose: (1) evaluation compound IV is to maintaining the effect (blood-serum P SA reaction and blood-serum P SA progress) of the Serum PSA level in the male sex who suffers from metastatic castration resistance prostate cancer (mCRPC) who carries out androgen-deprivation therapy; (2) effect of evaluation compound IV to free serum testosterone levels; (3) effect of evaluation compound IV to serum SHBG; (4) effect of evaluation compound IV to the total testosterone of serum; (5) effect of evaluation compound IV to adrenal androgen prohormone (DHEA and DHEAS); (6) effect of the development that evaluation compound IV shifts new bone; (7) evaluation compound IV shifts the effect of (internal organ and lymph node) to soft tissue; (8) effect of evaluation compound IV to bone dependent event; (9) effect of evaluation compound IV to Bone turnover marker; (10) evaluate the incidence of disease and the frequency of hot flash in the male sex who takes compound IV; (11) safety and tolerance in the male sex who suffers from prostate cancer who carries out androgen-deprivation therapy that evaluation compound IV had lost efficacy at ADT.
In this research, recruit and there is metastatic disease 75 experimenters that suffer from castration resistance prostate cancer of the radiography evidence of (T is any-N is any-M1).These experimenters have the intermediate value life expectancy that is less than 20 months, than the more serious disease of other experimenter of suffering from advanced prostate cancer of recruiting in research before.Before all experimenters, used androgen-deprivation therapy (ADT) to treat, ADT has been responded and current blood-serum P SA>2ng/mL, or >2ng/mL and represent that the minimum of realizing when carrying out ADT has 25% increase.Experimenter maintains and carries out ADT in whole research.
Each experimenter accepts every daily dose of Orally administered 125mg compound IV, 250mg compound IV or 500mg compound IV, until their blood-serum P SA when starting to evaluate with twice after compound IV treatment continuous blood-serum P SA from minimum increase at least 25% and 2ng/mL.
Compound IV 125mg and 500mg tablet are with micronized compound IV drug substance and 1% lauryl sodium sulfate (SDS) preparation, and supply is in 50 high density polyethylene (HDPE) on chip (HDPE) bottles.
Recruitment in this research is staggered 1 cycle (30 days) so that front 25 experimenters are recruited to 125mg compound IV dosage group.The incidence of disease for VTE event (VTE) is evaluated these experimenters.When last experimenter in 125mg compound IV dosage group has completed 1 treatment cycle (30 days) in described dosage group and had the acceptable VTE incidence of disease (being less than 3 people) at that time in described dosage group, recruit the recruitment that starts 250mg compound IV dosage group.For the incidence of disease of VTE, evaluate these experimenters.When all 25 experimenters in 250mg compound IV dosage group have completed 1 treatment cycle (30 days) in described dosage group and had the acceptable VTE incidence of disease (being less than 3 people) at that time in described dosage group, start the recruitment in 500mg compound IV dosage group (25 experimenters).
500mg dosage expectancy increases serum SHBG and causes the remarkable minimizing of free serum testosterone.Compared with low dosage (125mg and 250mg) expection, increase serum SHBG, but reach less degree, and be added into the minimum effective dose of determining compound IV generation blood-serum P SA reaction in scheme.These dosage may also have direct effect in reducing the suprarenal gland generation of androgen precurosor as DHEAS and DHEA, and described androgen precurosor can be by prostate gland cancer cell for generation of testosterone or dihydrotestosterone (DHT).
125mg compound IV, 250mg compound IV or 500mg compound IV are applied to all experimenters in this research every day, until they developed blood-serum P SA progress (blood-serum P SA start with twice continuous sampling after compound IV treatment during the time, increased at least 25% and than the high 2ng/mL of minimum).In the time of the 90th day, if not having blood-serum P SA, experimenter do not confirmed when evaluating for the second time from least 50% minimizing and this point of baseline, so described experimenter will give up the study of.In when research, the total duration that does not demonstrate administration in the experimenter of blood-serum P SA progress can be to be greater than 360 days.
The experimenter who demonstrates blood-serum P SA progress when starting to evaluate continuously with twice after compound IV treatment gives up the study of.In the time of the 90th day, when twice continuous sampling, do not show that blood-serum P SA gives up the study of from any experimenter of the minimizing of baseline >50%.
After experimenter has demonstrated blood-serum P SA progress, described experimenter keeps drug administration 30 days and has the blood-serum P of following up a case by regular visits to SA evaluation.If blood-serum P SA progress unconfirmed when making a house call specifically, experimenter keeps under study for action and continuation compound IV administration so.If make a house call middle confirmation blood-serum P SA progress specifically, experimenter gives up the study of and studies and finishes to make a house call evaluation so.
In the time of the 15th day, the 30th day and the evaluation of carrying out the total testosterone of serum, free serum testosterone, serum SHGB and blood-serum P SA concentration for every 30 days, until their blood-serum P SA start with twice continuous sampling after compound IV treatment during the time from minimum increase at least 25% and 2ng/mL.When finishing, baseline (the 1st day), the 90th day and research evaluates Bone turnover marker.
When finishing, baseline (the 1st day), the 30th day, the 60th day, the 90th day and research evaluates the incidence of disease and the frequency of hot flash.
In the time of the 0th day and every CT scan that carries out belly/pelvis for 90 days until research finishes evaluation tumour progression and soft tissue or visceral metastases.
In the time of the 0th day and within every 90 days, carry out bone scanning and evaluate until research finishes the development that new bone shifts.
Main terminal: during by the 90th day, blood-serum P SA has the experimenter's who declines from baseline 50% ratio (evaluating to confirm by the second blood-serum P SA after 30 days) (having the confirmation of following up a case by regular visits to by the 120th day).
Secondary endpoints: (1) reaches the time of blood-serum P SA progress; (2) blood-serum P SA has the experimenter's who declines from baseline >=90% ratio; (3) blood-serum P SA has the experimenter's who declines from baseline >=30% ratio; (4) variation of free serum testosterone levels; (5) variation of level of SHBG; (6) variation of the total testosterone levels of serum; (7) variation of DHEA and DHEAS level; (8) by RECIST1.1 (soft tissue) or time that reaches progress (TTP) of evaluating by PCWG2 (bone transfer); (9) by RECIST1.1 (soft tissue) or the progresson free survival (PFS) evaluated by PCWG2 (bone transfer); (10) variation of Bone turnover marker level; (11) hot flash is from the incidence of disease of baseline and the variation of frequency; (12) reach the time of SRE new or that worsen; (13) safety and tolerance in the male sex who suffers from prostate cancer that evaluation compound IV had lost efficacy at ADT.
In order to minimize the risk of the VTE in described research: (1) have the individual of abnormal blood coagulation or thrombotic diseases (vein or arterial thrombus sexual behavior part, as the medical history of apoplexy, DVT form (DVT) and/or pulmonary embolism (PE)) or the experimenter of family's medical history will be excluded as described in outside research.(2) there is the protein C reactivity of activation and the factor VLeiden sudden change of the modification of <2.5, any experimenter of existence who is less than Serum Homocysteine Level, anti-phospholipid antibody or the prothrombin gene mutation of normal 80% antithrombase level, >7 micromoles per liter will be excluded outside described research.(3) if carrying out aspirin or other anticoagulant therapy, all experimenters that recruit in described research will not need every day and take the aspirin of 81mg.Although the report about the validity of aspirin prevention VTE is always disputable, nearest document support supposes below, and, for VTE prevention, low dosage aspirin is equally effective with low molecular weight heparin.(4) all experimenters that recruit in described research will evaluate their VTE risk with Caprini venous thromboembolism risk assessment instrument.Experimenter's VTE risk will be evaluated at every turn when making a house call, if differentiate the variation of risk in research process, will formulate suitable prevention so.More particularly, the experimenter that experience makes experimenter become the high risk event (as needs are fixed, long bone fracture, acute injury, hospitalization, operation, radiation etc.) of VTE will tightly monitor and instruct their suitable preventive measure to minimize their VTE risk, and when indication, experimenter will treat with preventative anticoagulant therapy.(5) all thromboembolic events or cardiovascular SAE be considered at least may be relevant with compound IV therapy and will be included in test stopping rule, and do not consider researcher's attribute.
The experimenter that described research institute accepts is necessary:
There is castration resistance patients with prostate cancer, there is the radiography sign of metastatic disease (T is any-N is any-M1)
ADT (chemistry or operation) treatment at least 6 months have been used
The total testosterone of serum (<50ng/dL) with castration level
The history while carrying out ADT with blood-serum P SA reaction.What blood-serum P SA reaction was blood-serum P SA from the blood-serum P SA value before begin treatment is reduced by least 90% to <10ng/mL or blood-serum P SA (<0.2ng/mL) that can not detection level.
There is continuously blood-serum P SA and the Serum PSA level >2ng/mL of rising during evaluation twice of at least 2 weeks of being separated by, or >2ng/mL and have 25% increase higher than the minimum from ADT.If experimenter has carried out treatment and demonstrated blood-serum P SA progress with antiandrogen, so described experimenter will be required to stop described antiandrogen.Once described antiandrogen is stopped (antiandrogen is given up), described experimenter is separated by should have the Serum PSA level of at least two risings at least 2 weeks.
In whole research, carry out continuously ADT
Experimenter must agree to that (if also not carrying out anticoagulant therapy or aspirin) participates in whole duration of described research and continue 30 day every day after completing with compound IV administration taking 81mg aspirin at them.
The flow chart of descriptive study program is presented in Figure 25.
Clinical making a house call: potential research participant will make a house call for screening and assessment to clinical research facility place as required.Experimenter will be when recruiting (the 1st day) has relevant the making a house call of research during with the 15th day and the 30th day.Experimenter will return to from the 30th day to the 90th day clinic for every 30 days.Blood-serum P SA is reduced by least those experimenters of 50% from baseline and will still studies and will within the from the 90th to the 360th day every 30 days, return to clinic, and then within every 90 days after the 360th day, return, until their blood-serum P SA start with after compound IV treatment from minimum increase at least 25% and 2ng/mL, and evaluate to confirm that with the second blood-serum P SA described discovery result or their disease make progress (CT or bone scanning).
Following up a case by regular visits to makes a house call will carry out after dosage the last time for 30 days.
Blood-serum P SA in experimenter start with after compound IV treatment from minimum increase 2ng/mL and 25% time at least, described experimenter has met the standard of progression of disease.Yet, described experimenter should still study until after 30 days the property confirmed follow up a case by regular visits to blood-serum P SA.If described in follow up a case by regular visits to evaluation blood-serum P SA unconfirmed progress, so described experimenter should still study and continue to use compound IV administration.If described in follow up a case by regular visits to blood-serum P SA and confirmed that blood-serum P SA progress, so described experimenter should give up the study of and should studys end and make a house call and follow up a case by regular visits to and make a house call.
In the time of the 90th day, do not demonstrate blood-serum P SA and from any experimenter of baseline minimizing >50%, the confirmation 30 days with blood-serum P SA after the 90th day is evaluated.Described experimenter should keep taking drugs and until the property confirmed evaluation after the 90th day.When the property confirmed evaluation, if blood-serum P SA reduces >50% from baseline, so described experimenter will still study and continue to use compound IV administration.If in the property confirmed evaluation, blood-serum P SA does not reduce >50% from baseline, so described experimenter will give up the study of owing to lacking effect.Should study and finish make a house call and follow up a case by regular visits to and make a house call.
As by CT imaging (RECIST1.1 standard) or when the bone scanning viewed two new pathologies prove, show that the experimenter of the sign of progression of disease must give up the study of.
Efficiency analysis, blood-serum P SA and blood-serum P SA reaction
Blood-serum P SA reaction in the time of the 90th day will be main result and will evaluate for all experimenters.Blood-serum P SA reaction is by the decline from baseline >50% that is defined as confirming by the second blood-serum P SA value in 14 days.Main purpose is the blood-serum P SA reactivity of evaluating in the male sex who suffers from mCRPC who maintains ADT who accepts compound IV.
By estimate to have blood-serum P SA reaction experimenter ratio and calculate accurate 95%Blyth-Still-Casella confidence interval [20].
Described estimation will be carried out among following:
(1) be intended to the experimenter in treatment (ITT) colony, it is non-reactor that the experimenter who wherein exited before evaluation in the 90th day is considered to, and
(2) experimenter in effect valuable (EE) colony.
The diagram of the variation percentage of blood-serum P SA from baseline to each PSA evaluation (wherein focusing on evaluation in the 90th day) is described via waterfull Curve figure as described below.
To calculate the variation percentage of blood-serum P SA from baseline to each evaluation, and yaxle will represent to change percentage, x axle declines from the minimum percent of blood-serum P SA (for a certain or some experimenter, this may be to increase potentially) to the largest percentage that declines being having each independent experimenter's a bar and these order.
Blood-serum P SA progress
Blood-serum P SA progress is by the PCWG2 standard definition [21] by showing below.PCWG2 standard need to be confirmed doubtful blood-serum P SA progress for 3 to 4 weeks after the Serum PSA level of the possible progress of indication in evaluation.
To by Kapp orchid-Meyer method, estimate PSA progresson free survival and will build 95% relevant confidence interval.Experimenter's progresson free survival will be until the time on first date relevant to the progress of confirming or death from the first dosage of research.Exiting or lose the experimenter who follows up a case by regular visits to will examine according to the date of its last contact.If realize intermediate value, the intermediate value estimated value of PSA progresson free survival will be estimated so.
By estimating by Kapp orchid-Meyer method, reach the time of PSA progress and will build 95% relevant confidence interval.The time that experimenter reaches progress will be until the time on first date being associated with the progress of confirming from the first dosage of research medicament.Experimenter dead before progress will examine according to the dead date.Exiting or lose the experimenter who follows up a case by regular visits to will examine according to the date of its last contact.If realize intermediate value, so estimation is reached to the intermediate value estimated value of the time of progress.
If realize intermediate value, the intermediate value estimated value of serum PSA progresson free survival will be estimated so.
Blood-serum P SA progress (PCWG2 definition):
If blood-serum P SA initially declines from baseline, so when blood-serum P SA has 25% or larger increase and 2ng/ml or more while definitely increasing from minimum, as the date that progress occurs, but should confirm by the second blood-serum P SA value obtaining after 3 or more weeks.
If there is no blood-serum P SA from the decline of baseline, so when blood-serum P SA had 25% or larger increase and 2ng/ml or more while definitely increasing after 12 weeks, as the date that progress occurs, but should confirm by the second blood-serum P SA value obtaining after 3 or more weeks.
Free serum testosterone
The variation of the evaluation by evaluation free serum testosterone levels from baseline to each plan.If data are confirmed as normal distribution, will with paired t-, check the variation of the evaluation from baseline to each plan and change percentage so; Otherwise, will use accurate Wilkerson (Wilcoxon) signed rank test carry out the variation of the evaluation of comparison from baseline to each plan and change percentage.Described evaluation will be carried out until experimenter's decreased number arrives lower than 5.Mixed model repeated merasurements model can be used for probing into every group of interior temporal evolution.Experimenter will be considered to chance mechanism.
Serum SHBG
The variation of the evaluation by evaluation level of SHBG from baseline to each plan.If data are confirmed as normal distribution, will with paired t-, check the variation of the evaluation from baseline to each plan and change percentage so; Otherwise, by the variation of the evaluation that comes comparison from baseline to each plan with accurate Wilkerson signed rank test and variation percentage.Described evaluation will be carried out until experimenter's decreased number arrives lower than 5.Mixed model repeated merasurements model can be used for probing into every group of interior temporal evolution.Experimenter will be considered to chance mechanism.
The total testosterone of serum
The variation of the evaluation by evaluation level of serum testosterone from baseline to each plan.If data are confirmed as normal distribution, will with paired t-, check the variation of the evaluation from baseline to each plan and change percentage so; Otherwise, by the variation of the evaluation that comes comparison from baseline to each plan with accurate Wilkerson signed rank test and variation percentage.Described evaluation will be carried out until experimenter's decreased number arrives lower than 5.Mixed model repeated merasurements model can be used for probing into every group of interior temporal evolution.Experimenter will be considered to chance mechanism.
DHEA and DHEAS
The variation of the evaluation from baseline to each plan by evaluation DHEA and DHEAS level.If data are confirmed as normal distribution, will with paired t-, check the variation of the evaluation from baseline to each plan and change percentage so; Otherwise, by the variation of the evaluation that comes comparison from baseline to each plan with accurate Wilkerson signed rank test and variation percentage.Described evaluation will be carried out until experimenter's decreased number arrives lower than 5.Mixed model repeated merasurements model can be used for probing into every group of interior temporal evolution.Experimenter will be considered to chance mechanism.
Progression of disease: soft tissue progress (RECIST1.1)
RECIST1.1 standard will be for evaluating progress and reaction.To among experimenter, estimate as following defined TTP and PFS.
To estimate progresson free survival (PFS) and will build 95% relevant confidence interval by Kapp orchid-Meyer method.Experimenter's progresson free survival will be until the time of the taking of evidence of progress or death from the first dosage of research medicament.Exiting or lose the experimenter who follows up a case by regular visits to will examine according to the date of its last contact.
If realize intermediate value, the intermediate value estimated value of PFS will be estimated so.
To by Kapp orchid-Meyer method, estimate to reach the time (TTP) of progress and will build 95% relevant confidence interval.The time that experimenter reaches progress will be until the time of the taking of evidence of progress from the first dosage of research medicament.Experimenter dead before progress will examine according to date of death.Exiting or lose the experimenter who follows up a case by regular visits to will examine according to the date of its last contact.
If realize intermediate value, so estimation is reached to the intermediate value estimated value of the time of progress.
To determine experimenter's optimum response and will estimate the ratio of CR, PR (PR+CR), SD and PD, and calculate accurate 95%Blyth-Still-Casella confidence interval.
Bone progress
To among the experimenter presenting measurable bone scanning transfer, estimate as following defined TTP and PFS.
To estimate progresson free survival (PFS) and will build 95% relevant confidence interval by Kapp orchid-Meyer method.Experimenter's progresson free survival will be until the time of the taking of evidence of progress or death from the first dosage of research medicament.Exiting or lose the experimenter who follows up a case by regular visits to will examine according to the date of its last contact.
If realize intermediate value, the intermediate value estimated value of PFS will be estimated so.
To by Kapp orchid-Meyer method, estimate to reach the time (TTP) of progress and will build 95% relevant confidence interval.The time that experimenter reaches progress will be until the time of the taking of evidence of progress from the first dosage of research medicament.Experimenter dead before progress will examine according to the dead date.Exiting or lose the experimenter who follows up a case by regular visits to will examine according to the date of its last contact.
If realize intermediate value, so estimation is reached to the intermediate value estimated value of the time of progress.
To determine experimenter's optimum response and will estimate the ratio of CR, PR (PR+CR), SD and PD, and calculate accurate 95%Blyth-Still-Casella confidence interval.
Bone turnover marker
The variation of the evaluation by every kind of Bone turnover marker in each treatment group of evaluation from baseline to each plan.Mean value, standard deviation, intermediate value, minimum and maximum Bone turnover marker level are summed up to by each place in these time points.Equally by the variation of summing up from baseline to each time point.Whether t-check will significantly be different from zero about the variation from baseline to each time point at a group build-in test in pairs.To carry out described test for ITT colony.To carry out described test and will carry out LOCF analysis equally for viewed situation.Mixed model repeated merasurements model can be used for probing in every group over time.Experimenter will be considered to chance mechanism.
Hot flash
To experimenter, inquire with regard to hot flash event (incidence of disease and frequency).The particular problem of puing question to and the definition of seriousness are included in Appendix D.
Experience the experimenter's of any hot flash ratio and will make form by treatment group.Experience weekly or more frequently the experimenter's of hot flash ratio and will make form by treatment group.Every day or the ratio that experiences more frequently the experimenter of hot flash will be made form by treatment group.Experience repeatedly the experimenter's of hot flash ratio every day and will make form by treatment group.
Experience moderate to the experimenter's of very serious hot flash ratio will be made form by treatment group.The serious experimenter's to very serious hot flash of experience ratio will be made form by treatment group.
Offset table will represent the variation of seriousness from baseline to each evaluation.
Bone dependent event (SRE)
SRE comprises pathologic fracture, spinal compression and to the radiation of bone or operating composite end points.
By estimating by Kapp orchid-Meyer method, without bone photo, close event time and will build 95% relevant confidence interval.Experimenter's will be until the time of the taking of evidence of new SRE or death from the first dosage of research medicament without bone photo pass event time.Exiting or lose the experimenter who follows up a case by regular visits to will examine according to the date of its last contact.Described analysis will repeat under the event being defined as any SRE new or that worsen or death.
If realize intermediate value, will estimate so to close without bone photo the intermediate value estimated value of event time (SRE new or that worsen).
By the time of the bone dependent event of estimating to reach new by Kapp orchid-Meyer method, and 95% relevant confidence interval will be built.The time that experimenter reaches new bone dependent event will be until the time of the taking of evidence of new bone dependent event from the first dosage of research medicament.Experimenter dead before new bone dependent event will examine according to the dead date.Exiting or lose the experimenter who follows up a case by regular visits to will examine according to the date of its last contact.Described analysis will repeat under the event being defined as SRE new or that worsen.
If realize intermediate value, so by the intermediate value estimated value of the time of the SRE that estimates to reach new (SRE new or that worsen).
Embodiment 28
Secondary hormonotherapy for metastatic castration resistance prostate cancer (mCRPC)
For the indication secondary hormonotherapy proposing for metastatic castration resistance prostate cancer (mCRPC), estradiol, ethinyl estradiol, steroids estrogen agonist and on-steroidal estrogen agonist are studied to (research 6).
Estradiol, ethinyl estradiol, steroids estrogen agonist and on-steroidal estrogen agonist show that serum SHBG increases and free serum testosterone are reduced to the level lower than the level of having observed by LHRH activator or antagonist or operation castration.Compare with leuprorelin acetate treatment group, estradiol, ethinyl estradiol, steroids estrogen agonist and on-steroidal estrogen agonist show Bone turnover marker from baseline minimizing and during suffering from the male sex of advanced prostate cancer, have the lower hot flash adverse events incidence of disease.
Studied estradiol, ethinyl estradiol, steroids estrogen agonist and on-steroidal estrogen agonist as secondary hormonotherapy to maintaining Serum PSA level in the male sex who suffers from metastatic castration resistance prostate cancer of androgen-deprivation therapy and the effect of free serum testosterone levels.The effect that described research evaluation estradiol, ethinyl estradiol, steroids estrogen agonist and on-steroidal estrogen agonist make progress to carry out blood-serum P SA reaction in the male sex who suffers from mCRPC of ADT and blood-serum P SA with LHRH activator, lhrh antagonist or orchiectomy.Described research also evaluate estradiol, ethinyl estradiol, steroids estrogen agonist and on-steroidal estrogen agonist compared with the VTE risk of low dosage.Secondary endpoints comprises that free serum testosterone levels, adrenal androgen precursor produce (DHEA and DHEAS level), progresson free survival and bone dependent event (SRE).
Research purpose: (1) evaluation estradiol, ethinyl estradiol, steroids estrogen agonist and on-steroidal estrogen agonist are to maintaining the effect (blood-serum P SA reaction and blood-serum P SA make progress) of the Serum PSA level in the male sex who suffers from metastatic castration resistance prostate cancer (mCRPC) of androgen-deprivation therapy; (2) evaluation estradiol, ethinyl estradiol, steroids estrogen agonist and the effect of on-steroidal estrogen agonist to free serum testosterone levels; (3) evaluation estradiol, ethinyl estradiol, steroids estrogen agonist and the effect of on-steroidal estrogen agonist to serum SHBG; (4) evaluation estradiol, ethinyl estradiol, steroids estrogen agonist and the effect of on-steroidal estrogen agonist to the total testosterone of serum; (5) evaluation estradiol, ethinyl estradiol, steroids estrogen agonist and the effect of on-steroidal estrogen agonist to adrenal androgen prohormone (DHEA and DHEAS); (6) effect of the development that evaluation estradiol, ethinyl estradiol, steroids estrogen agonist and on-steroidal estrogen agonist shift new bone; (7) evaluation estradiol, ethinyl estradiol, steroids estrogen agonist and on-steroidal estrogen agonist shift the effect of (internal organ and lymph node) to soft tissue; (8) evaluation estradiol, ethinyl estradiol, steroids estrogen agonist and the effect of on-steroidal estrogen agonist to bone dependent event; (9) evaluation estradiol, ethinyl estradiol, steroids estrogen agonist and the effect of on-steroidal estrogen agonist to Bone turnover marker; (10) incidence of disease and the frequency of hot flash in the male sex of evaluation estradiol, ethinyl estradiol, steroids estrogen agonist and on-steroidal estrogen agonist; (11) safety and tolerance in the male sex who suffers from prostate cancer who carries out androgen-deprivation therapy that evaluation estradiol, ethinyl estradiol, steroids estrogen agonist and on-steroidal estrogen agonist had lost efficacy at ADT.
In this research, recruit and there is metastatic disease 75 experimenters that suffer from castration resistance prostate cancer of the radiography evidence of (T is any-N is any-M1).These experimenters have the intermediate value life expectancy that is less than 20 months, than the more serious disease of other experimenter of suffering from advanced prostate cancer of recruiting in research before.Before all experimenters, used androgen-deprivation therapy (ADT) to treat, ADT has been responded and current blood-serum P SA>2ng/mL, or >2ng/mL and represent there is 25% increase higher than carrying out the minimum that ADT realizes.Experimenter maintains and carries out ADT in whole research.
Each experimenter accepts every daily dose of Orally administered 125mg, 250mg or 500mg estradiol, ethinyl estradiol, steroids estrogen agonist or on-steroidal estrogen agonist, until their blood-serum P SA when starting to evaluate with twice continuous blood-serum P SA after estradiol, ethinyl estradiol, steroids estrogen agonist or the treatment of on-steroidal estrogen agonist from minimum increase at least 25% and 2ng/mL.
500mg dosage expectancy increases serum SHBG and causes the remarkable minimizing of free serum testosterone.Compared with low dosage (125mg and 250mg) expection, increase serum SHBG, but to less degree, and be added into the minimum effective dose of determining estradiol, ethinyl estradiol, steroids estrogen agonist and on-steroidal estrogen agonist generation blood-serum P SA reaction in scheme.These dosage may also have direct effect in reducing the suprarenal gland generation of androgen precurosor as DHEAS and DHEA, and described androgen precurosor can be by prostate gland cancer cell for generation of testosterone or dihydrotestosterone (DHT).
125mg, 250mg, 500mg estradiol, ethinyl estradiol, steroids estrogen agonist or on-steroidal estrogen agonist are applied to all experimenters in described research every day, until they developed blood-serum P SA progress (blood-serum P SA start with twice continuous sampling after estradiol, ethinyl estradiol, steroids estrogen agonist or the treatment of on-steroidal estrogen agonist during the time from minimum increase at least 25% and than the high 2ng/mL of minimum).In the time of the 90th day, if experimenter's blood-serum P SA not from baseline be reduced by least 50% and this point when evaluating for the second time, confirmed, so described experimenter will give up the study of.In when research demonstrates the experimenter of blood-serum P SA progress, the total duration of administration can not be to be greater than 360 days.
In the time of the 15th day, the 30th day and the evaluation of carrying out the total testosterone of serum, free serum testosterone, serum SHGB and blood-serum P SA concentration for every 30 days, until their blood-serum P SA start with twice continuous sampling after compound IV treatment during the time from minimum increase at least 25% and 2ng/mL.When finishing, baseline (the 1st day), the 90th day and research evaluates Bone turnover marker.
When finishing, baseline (the 1st day), the 30th day, the 60th day, the 90th day and research evaluates the incidence of disease and the frequency of hot flash.
In the time of the 0th day and every CT scan that carries out belly/pelvis for 90 days until research finishes evaluation tumour progression and soft tissue or visceral metastases.
In the time of the 0th day and within every 90 days, carry out bone scanning and evaluate until research finishes the development that new bone shifts.
Main terminal: during by the 90th day, blood-serum P SA has the experimenter's who declines from baseline 50% ratio (evaluating to confirm by the second blood-serum P SA after 30 days) (having the confirmation of following up a case by regular visits to by the 120th day).
Secondary endpoints: (1) reaches the time of blood-serum P SA progress; (2) blood-serum P SA has the experimenter's who declines from baseline >=90% ratio; (3) blood-serum P SA has the experimenter's who declines from baseline >=30% ratio; (4) variation of free serum testosterone levels; (5) variation of level of SHBG; (6) variation of the total testosterone levels of serum; (7) variation of DHEA and DHEAS level; (8) by RECIST1.1 (soft tissue) or time that reaches progress (TTP) of evaluating by PCWG2 (bone transfer); (9) by RECIST1.1 (soft tissue) or the progresson free survival (PFS) evaluated by PCWG2 (bone transfer); (10) variation of Bone turnover marker level; (11) hot flash from baseline the incidence of disease and the variation of frequency; (12) reach the time of SRE new or that worsen; (13) safety and tolerance in the male sex who suffers from prostate cancer that evaluation compound IV had lost efficacy at ADT.
Free serum testosterone
The variation of the evaluation by evaluation free serum testosterone levels from baseline to each plan.If data are confirmed as normal distribution, will with paired t-, check the variation of the evaluation from baseline to each plan and change percentage so; Otherwise, by the variation of the evaluation that comes comparison from baseline to each plan with accurate Wilkerson signed rank test and variation percentage.Described test will be carried out until experimenter's decreased number arrives lower than 5.Mixed model repeated merasurements model can be used for probing into every group of interior temporal evolution.Experimenter will be considered to chance mechanism.
Serum SHBG
The variation of the evaluation by evaluation level of SHBG from baseline to each plan.If data are confirmed as normal distribution, will with paired t-, check the variation of the evaluation from baseline to each plan and change percentage so; Otherwise, by the variation of the evaluation that comes comparison from baseline to each plan with accurate Wilkerson signed rank test and variation percentage.Described test will be carried out until experimenter's decreased number arrives lower than 5.Mixed model repeated merasurements model can be used for probing into every group of interior temporal evolution.Experimenter will be considered to chance mechanism.
The total testosterone of serum
The variation of the evaluation by evaluation level of serum testosterone from baseline to each plan.If data are confirmed as normal distribution, will with paired t-, check the variation of the evaluation from baseline to each plan and change percentage so; Otherwise, by the variation of the evaluation that comes comparison from baseline to each plan with accurate Wilkerson signed rank test and variation percentage.Described test will be carried out until experimenter's decreased number arrives lower than 5.Mixed model repeated merasurements model can be used for probing into the temporal evolution in every group.Experimenter will be considered to chance mechanism.
DHEA and DHEAS
The variation of the evaluation from baseline to each plan by evaluation DHEA and DHEAS level.If data are confirmed as normal distribution, will with paired t-, check the variation of the evaluation from baseline to each plan and change percentage so; Otherwise, by the variation of the evaluation that comes comparison from baseline to each plan with accurate Wilkerson signed rank test and variation percentage.Described test will be carried out until experimenter's decreased number arrives lower than 5.Mixed model repeated merasurements model can be used for probing in every group over time.Experimenter will be considered to chance mechanism.
Progression of disease: soft tissue progress (RECIST1.1)
RECIST1.1 standard will be for evaluating progress and reaction.To among experimenter, estimate as following defined TTP and PFS.
To estimate progresson free survival (PFS) and will build 95% relevant confidence interval by Kapp orchid-Meyer method.Experimenter's progresson free survival will be until the time of the taking of evidence of progress or death from the first dosage of research medicament.Exiting or lose the experimenter who follows up a case by regular visits to will examine according to the date of its last contact.
If realize intermediate value, the intermediate value estimated value of PFS will be estimated so.
To by Kapp orchid-Meyer method, estimate to reach the time (TTP) of progress and will build 95% relevant confidence interval.The time that experimenter reaches progress will be until the time of the taking of evidence of progress from the first dosage of research medicament.Experimenter dead before progress will examine according to the dead date.Exiting or lose the experimenter who follows up a case by regular visits to will examine according to the date of its last contact.
If realize intermediate value, so estimation is reached to the intermediate value estimated value of the time of progress.
To determine experimenter's optimum response and will estimate the ratio of CR, PR (PR+CR), SD and PD, and calculate accurate 95%Blyth-Still-Casella confidence interval.
Bone progress
To among the experimenter presenting measurable bone scanning transfer, estimate as following defined TTP and PFS.
To estimate progresson free survival (PFS) and will build 95% relevant confidence interval by Kapp orchid-Meyer method.Experimenter's progresson free survival will be until the time of the taking of evidence of progress or death from the first dosage of research medicament.Exiting or lose the experimenter who follows up a case by regular visits to will examine according to the date of its last contact.
If realize intermediate value, the intermediate value estimated value of PFS will be estimated so.
To by Kapp orchid-Meyer method, estimate to reach the time (TTP) of progress and will build 95% relevant confidence interval.The time that experimenter reaches progress will be until the time of the taking of evidence of progress from the first dosage of research medicament.Experimenter dead before progress will examine according to the dead date.Exiting or lose the experimenter who follows up a case by regular visits to examined according to the date finally contacting at it.
If realize intermediate value, so estimation is reached to the intermediate value estimated value of the time of progress.
To determine experimenter's optimum response and will estimate the ratio of CR, PR (PR+CR), SD and PD, and calculate accurate 95%Blyth-Still-Casella confidence interval.
Bone turnover marker
The variation of the evaluation by every kind of Bone turnover marker in each treatment group of evaluation from baseline to each plan.Mean value, standard deviation, intermediate value, minimum and maximum Bone turnover marker level are summed up to by each place in these time points.Equally by the variation of summing up from baseline to each time point.Whether t-check is different from zero by check in a group significantly about the variation from baseline to each time point in pairs.To carry out this point for ITT colony.To carry out described test and will carry out LOCF analysis equally for viewed situation.Mixed model repeated merasurements model can be used for probing in every group over time.Experimenter will be considered to chance mechanism.
Hot flash
To experimenter, inquire with regard to hot flash event (incidence of disease and frequency).The particular problem of puing question to and the definition of seriousness are included in Appendix D.
Experience the experimenter's of any hot flash ratio and will make form by treatment group.Experience weekly or more frequently the experimenter's of hot flash ratio and will make form by treatment group.Every day or the ratio that experiences more frequently the experimenter of hot flash will be made form by treatment group.Experience repeatedly the experimenter's of hot flash ratio every day and will make form by treatment group.
Experience moderate to the experimenter's of very serious hot flash ratio will be made form by treatment group.The serious experimenter's to very serious hot flash of experience ratio will be made form by treatment group.
Offset table will represent the variation of seriousness from baseline to each evaluation.
Bone dependent event (SRE)
SRE comprises pathologic fracture, spinal compression and to the radiation of bone or operating composite end points.
By estimating by Kapp orchid-Meyer method, without bone photo, close event time and will build 95% relevant confidence interval.Experimenter's will be until the time of the taking of evidence of new SRE or death from the first dosage of research medicament without bone photo pass event time.Exiting or lose the experimenter who follows up a case by regular visits to will examine according to the date of its last contact.Described analysis will repeat under the event being defined as any SRE new or that worsen or death.
If realize intermediate value, will estimate so to close without bone photo the intermediate value estimated value of event time (SRE new or that worsen).
By the time of the bone dependent event of estimating to reach new by Kapp orchid-Meyer method and will build 95% relevant confidence interval.The time that experimenter reaches new bone dependent event will be until the time of the taking of evidence of new bone dependent event from the first dosage of research medicament.Experimenter dead before new bone dependent event will examine according to the dead date.Exiting or lose the experimenter who follows up a case by regular visits to will examine according to the date of its last contact.Described analysis will repeat under the event being defined as SRE new or that worsen.
If realize intermediate value, so by the intermediate value estimated value of the time of the SRE that estimates to reach new (SRE new or that worsen).
Although illustrated in this article and described some feature of the present invention, now those of ordinary skill in the art can expect many modifications, substitute, change and equivalent.Therefore, should be appreciated that, the claims of enclosing intention contains all these type of modifications and the change within the scope of term practicalness of the present invention.

Claims (39)

1. a method for the treatment of, suppress castration resistance prostate cancer (CRPC) and its symptom, reduce its incidence of disease, reduce its seriousness or suppress its progress or increase the male sex's who suffers from castration resistance prostate cancer survival rate, it comprises formula I compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose:
Wherein
Y is C (O) or CH 2;
R 1, R 2be hydrogen, halogen, hydroxyl, alkoxyl, cyano group, nitro, CF independently 3, N (R) 2, sulfonamide, SO 2r, alkyl, alkylhalide group, aryl, O-Alk-NR 5r 6or O-Alk-heterocycle, wherein said heterocycle be 3 yuan to heterocycle 7 yuan of replacements or unsubstituted, be optionally aromatic;
R 3, R 4be hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxyl, cyano group, nitro, CF independently 3, NHCOR, N (R) 2, sulfonamide, SO 2r, alkyl, alkylhalide group, aryl or shielded hydroxyl;
R is alkyl, hydrogen, alkylhalide group, two alkylhalide groups, three alkylhalide groups, CH 2f, CHF 2, CF 3, CF 2cF 3, aryl, phenyl, halogen, thiazolinyl, CN, NO 2or OH;
R 5and R 6be the alkyl of hydrogen, phenyl, 1 to 6 carbon atom, 3 yuan to 7 yuan cycloalkyl, 3 yuan to 7 yuan heterocycles, 5 yuan to 7 yuan aryl independently; Or R 5and R 6form 3 yuan to 7 rings together with nitrogen-atoms;
J and k are 1 to 4 independently; And
Alk is that the straight chained alkyl of 1 to 7 carbon is, the cyclic alkyl of the branched alkyl of 1 to 7 carbon or 3 to 8 carbon.
2. the method for claim 1, wherein said formula I compound is selected from:
3. the method for claim 1, wherein said formula I compound is compound IV:
4. the method for claim 1, wherein said castration resistance prostate cancer (CRPC) is metastatic CRPC (mCRPC).
5. the method for claim 1, wherein said castration is chemistry or operation castration (orchiectomy).
6. the method for claim 1, wherein said experimenter has prostate specific antigen (PSA) level high or that increase.
7. the method for claim 1, wherein said experimenter further accepts androgen-deprivation therapy (ADT).
8. the method for claim 1, uses described in wherein said compound and can not cause the side effect relevant to androgen-deprivation therapy (ADT).
9. method as claimed in claim 8, the group that wherein said side effect selects free the following to form: hot flash, gynecomastia, body fat increase, bone-loss, BMD reduces and risk of bone fracture increases.
10. the method for claim 1, wherein said compound or isomer, pharmaceutically acceptable salt, medicinal product, hydrate or its any combination be with every day 125mg, every day 250mg or every day 500mg dosage use.
11. 1 kinds of reductions suffer from the method for the Serum PSA level in the male subject of castration resistance prostate cancer (CRPC), and it comprises formula I compound or its isomer, pharmaceutically acceptable salt, medicinal product, hydrate or its any combination of administering therapeutic effective dose:
Wherein
Y is C (O) or CH 2;
R 1, R 2be hydrogen, halogen, hydroxyl, alkoxyl, cyano group, nitro, CF independently 3, N (R) 2, sulfonamide, SO 2r, alkyl, alkylhalide group, aryl, O-Alk-NR 5r 6or O-Alk-heterocycle, wherein said heterocycle be 3 yuan to heterocycle 7 yuan of replacements or unsubstituted, be optionally aromatic;
R 3, R 4be hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxyl, cyano group, nitro, CF independently 3, NHCOR, N (R) 2, sulfonamide, SO 2r, alkyl, alkylhalide group, aryl or shielded hydroxyl;
R is alkyl, hydrogen, alkylhalide group, two alkylhalide groups, three alkylhalide groups, CH 2f, CHF 2, CF 3, CF 2cF 3, aryl, phenyl, halogen, thiazolinyl, CN, NO 2or OH;
R 5and R 6be the alkyl of hydrogen, phenyl, 1 to 6 carbon atom, 3 yuan to 7 yuan cycloalkyl, 3 yuan to 7 yuan heterocycles, 5 yuan to 7 yuan aryl independently; Or R 5and R 6form 3 yuan to 7 rings together with nitrogen-atoms;
J and k are 1 to 4 independently; And
Alk is that the straight chained alkyl of 1 to 7 carbon is, the cyclic alkyl of the branched alkyl of 1 to 7 carbon or 3 to 8 carbon.
12. methods as claimed in claim 11, wherein said formula I compound is selected from:
13. methods as claimed in claim 11, wherein said formula I compound is compound IV:
14. methods as claimed in claim 11, wherein said castration resistance prostate cancer (CRPC) is metastatic CRPC (mCRPC).
15. methods as claimed in claim 11, wherein said experimenter further accepts androgen-deprivation therapy (ADT).
16. methods as claimed in claim 11, use described in wherein said compound and can not cause the side effect relevant to androgen-deprivation therapy (ADT).
17. methods as claimed in claim 16, the group that wherein said side effect selects free the following to form: hot flash, gynecomastia, body fat increase, bone-loss, BMD reduces and risk of bone fracture increases.
18. methods as claimed in claim 11, wherein said compound or isomer, pharmaceutically acceptable salt, medicinal product, hydrate or its any combination be with every day 125mg, every day 250mg or every day 500mg dosage use.
19. 1 kinds of reductions suffer from the method for the level of serum testosterone in the male subject of castration resistance prostate cancer (CRPC), and it comprises formula I compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose:
Wherein
Y is C (O) or CH 2;
R 1, R 2be hydrogen, halogen, hydroxyl, alkoxyl, cyano group, nitro, CF independently 3, N (R) 2, sulfonamide, SO 2r, alkyl, alkylhalide group, aryl, O-Alk-NR 5r 6or O-Alk-heterocycle, wherein said heterocycle be 3 yuan to heterocycle 7 yuan of replacements or unsubstituted, be optionally aromatic;
R 3, R 4be hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxyl, cyano group, nitro, CF independently 3, NHCOR, N (R) 2, sulfonamide, SO 2r, alkyl, alkylhalide group, aryl or shielded hydroxyl;
R is alkyl, hydrogen, alkylhalide group, two alkylhalide groups, three alkylhalide groups, CH 2f, CHF 2, CF 3, CF 2cF 3, aryl, phenyl, halogen, thiazolinyl, CN, NO 2or OH;
R 5and R 6be the alkyl of hydrogen, phenyl, 1 to 6 carbon atom, 3 yuan to 7 yuan cycloalkyl, 3 yuan to 7 yuan heterocycles, 5 yuan to 7 yuan aryl independently; Or R 5and R 6form 3 yuan to 7 rings together with nitrogen-atoms;
J and k are 1 to 4 independently; And
Alk is that the straight chained alkyl of 1 to 7 carbon is, the cyclic alkyl of the branched alkyl of 1 to 7 carbon or 3 to 8 carbon.
20. methods as claimed in claim 19, wherein said formula I compound is selected from:
21. methods as claimed in claim 19, wherein said formula I compound is compound IV:
22. methods as claimed in claim 19, wherein said castration resistance prostate cancer (CRPC) is metastatic CRPC (mCRPC).
23. methods as claimed in claim 19, wherein said level of serum testosterone is total serum testosterone levels, free level of serum testosterone, free serum testosterone percentage (free T%) or its combination.
24. methods as claimed in claim 19, wherein said experimenter has prostate specific antigen (PSA) level high or that increase.
25. methods as claimed in claim 19, wherein said experimenter further accepts androgen-deprivation therapy (ADT).
26. methods as claimed in claim 19, wherein said experimenter further accepts selective estrogen receptor modulators (SERM) part.
27. methods as claimed in claim 19, wherein said serum testosterone is reduced to lower than about 25ng/dL, 10ng/dL, 5ng/dL or 1ng/dL.
28. methods as claimed in claim 19, wherein said free serum testosterone percentage (free T%) is reduced to lower than approximately 1%, 0.5%, 0.25% and 0.05%.
29. methods as claimed in claim 19, use described in wherein said compound and can not cause the side effect relevant to androgen-deprivation therapy (ADT).
30. methods as claimed in claim 29, the group that wherein said side effect selects free the following to form: hot flash, gynecomastia, body fat increase, bone-loss, BMD reduces and risk of bone fracture increases.
31. methods as claimed in claim 19, wherein said compound or isomer, pharmaceutically acceptable salt, medicinal product, hydrate or its any combination be with every day 125mg, every day 250mg or every day 500mg dosage use.
32. 1 kinds of increases suffer from the method for the serum-concentration of property in the experimenter of castration resistance prostate cancer (CRPC) or steroid hormone haptoglobin (SHBG), and it comprises formula I compound or its isomer, pharmaceutically acceptable salt, medicinal product, polymorph, hydrate or its any combination of administering therapeutic effective dose:
Wherein
Y is C (O) or CH 2;
R 1, R 2be hydrogen, halogen, hydroxyl, alkoxyl, cyano group, nitro, CF independently 3, N (R) 2, sulfonamide, SO 2r, alkyl, alkylhalide group, aryl, O-Alk-NR 5r 6or O-Alk-heterocycle, wherein said heterocycle be 3 yuan to heterocycle 7 yuan of replacements or unsubstituted, be optionally aromatic;
R 3, R 4be hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxyl, cyano group, nitro, CF independently 3, NHCOR, N (R) 2, sulfonamide, SO 2r, alkyl, alkylhalide group, aryl or shielded hydroxyl;
R is alkyl, hydrogen, alkylhalide group, two alkylhalide groups, three alkylhalide groups, CH 2f, CHF 2, CF 3, CF 2cF 3, aryl, phenyl, halogen, thiazolinyl, CN, NO 2or OH;
R 5and R 6be the alkyl of hydrogen, phenyl, 1 to 6 carbon atom, 3 yuan to 7 yuan cycloalkyl, 3 yuan to 7 yuan heterocycles, 5 yuan to 7 yuan aryl independently; Or R 5and R 6form 3 yuan to 7 rings together with nitrogen-atoms;
J and k are 1 to 4 independently; And
Alk is that the straight chained alkyl of 1 to 7 carbon is, the cyclic alkyl of the branched alkyl of 1 to 7 carbon or 3 to 8 carbon.
33. methods as claimed in claim 32, wherein said formula I compound is selected from:
34. methods as claimed in claim 32, wherein said formula I compound is compound IV:
35. methods as claimed in claim 32, wherein said castration resistance prostate cancer (CRPC) is metastatic CRPC (mCRPC).
36. methods as claimed in claim 32, wherein said experimenter further accepts androgen-deprivation therapy (ADT).
37. methods as claimed in claim 32, use described in wherein said compound and can not cause the side effect relevant to androgen-deprivation therapy (ADT).
38. methods as claimed in claim 37, the group that wherein said side effect selects free the following to form: hot flash, gynecomastia, body fat increase, bone-loss, BMD reduces and risk of bone fracture increases.
39. methods as claimed in claim 32, wherein said compound or isomer, pharmaceutically acceptable salt, medicinal product, hydrate or its any combination be with every day 125mg, every day 250mg or every day 500mg dosage use.
CN201280051979.4A 2011-08-23 2012-08-23 Estrogen receptor ligands and methods of use thereof Pending CN103957706A (en)

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