CN1646479A

CN1646479A - Irreversible selective androgen receptor modulators and methods of use thereof

Info

Publication number: CN1646479A
Application number: CNA038047187A
Authority: CN
Inventors: 詹姆斯·多尔顿; 杜安·D.·米勒; 程奇元; 何雅丽; 米切尔·S.·斯坦纳; 卡伦·A.·韦韦尔卡
Original assignee: University of Tennessee Research Foundation
Current assignee: University of Tennessee Research Foundation
Priority date: 2002-02-28
Filing date: 2003-02-24
Publication date: 2005-07-27
Also published as: TW200304806A; WO2003074473A3; EP1487783A4; HRP20040851A2; MXPA04008412A; JP2005519111A; EP1487783A2; KR20040104463A; EA200401121A1; WO2003074473A2; AU2003214971A1; CA2476651A1; IL163742A0

Abstract

In an embodiment, the invention provides an androgen receptor target agent (ARTA). The target agent defines a novel subset compound of a selective androgen receptor modulator (SARM). The androgen receptor modulator compound has unexpected anti-androgen activity of a non-steroidal ligand for an androgen receptor. In an embodiment, the androgen receptor modulator compound is non-reversibly combined with the androgen receptor. In another embodiment, the androgen receptor modulator compound is an androgen receptor antagonist which is non-reversibly combined with the androgen receptor. In another embodiment, the androgen receptor modulator compound is an alkylating agent. The androgen receptor modulator compound, which is a monomer or a composition, is useful for following situations: a) male contraception; b) treatment of various hormone relative diseases, such as diseases related to male androgen degeneration (ADAM), for example, fatigue, dumps, libido reduction, sexual disorder, erectile dysfunction, hypogonadism, osteoporosis, alopecia, anaemia, adiposis, muscle consumption, sclerotin reduction, benign prostatic hyperplasia, changes in emotion and discernment, and prostate cancer; c) treatment of diseases related to female androgen degeneration (ADIF), such as sexual disorder, libido reduction, hypogonadism, muscle consumption, sclerotin reduction, osteoporosis, changes in emotion and discernment, dumps, anaemia, alopecia, adiposis, adenomyosis, breast cancer, uterus cancer, and ovary cancer; d) treatment and/or prevention of acute and/or chronic muscle consumption; e) prevention and/or treatment of xeroma; f) oral androgen replacing treatment; g) reducing an incidence rate of prostate cancer, interrupting or accelerating degradation of prostate cancer; and/or h) inducing apoptosis of cancer cells.

Description

Irreversible selective androgen receptor modulators and using method thereof

Statement of government interest

The present invention is by all or part of support of government, the license number R29 CA068096 that authorizes in National Cancer Institute (NationalCancer Institute), NIH (National Institute of Health), and study under the project of the license number RI5 HD35329 that authorizes of state-run children's health and human development institute (National Institute of Child Health and Human Development), NIH (National Institute of Health).Government can have established right of the present invention.

Invention field

The present invention relates to androgen receptor target agent (ARTA), they demonstrate the androgen antagonist activity of the non-steroidal ligands of androgen receptor, and/or the irreversible fixation of itself and androgen receptor.What the target agent defined is a new subclass compound of those SARM (SARM), and they are useful to following situation: a) male contraceptive; B) treatment of various hormone associated conditions is for example with male male sex hormone decline in old age (ADAM) diseases associated; C) to the treatment of female male sex hormone decline (ADIF) diseases related; D) treating and/or preventing acute and/or chronic muscle wasting illness (condition); E) prevent and/or treat the dry eyes illness; F) oral androgenic alternative medicine; G) reduce prostate cancer sickness rate, interrupt or impel the deterioration of prostate cancer; And/or h) apoptosis of inducing cancer cell.

Background of invention

Androgen receptor (" AR ") is a part activated transcription regulatory protein, and it mediates male sexual development and function by its endogenous androgenic activity.Male sex hormone is commonly called male hormone.Male sex hormone be produce in vivo by testis and adrenal cortex or in the laboratory synthetic steroid.Androgenic steroids plays an important role in many physiological processs, described process comprises the growth that male sex character such as muscle and bone amount (bone mass), prostate gland growth, spermatogeny and male hair distribute and keeps (Matsumoto, Endocrinol, Met.Clin.N.Am.23:857-75 (1994)).Endogenous steroid male sex hormone comprises testosterone and dihydrotestosterone (" DHT ").Testosterone is the main steroid by testicular secretion, and is the main circulation male sex hormone of finding in male blood plasma.In many peripheral tissues, testosterone is converted into DHT by the enzyme 5.Therefore think that for most of androgenic effects, DHT plays a part amboceptor in born of the same parents people such as (, Molec.Endocrinol.9:208-18 (1995)) Zhou.Other steroid male sex hormone comprises the ester of testosterone, as cipionate, propionic ester, phenylpropionic acid ester, cyclopentanepropanoiacid acid ester, isocarporate, heptanoate and decylate, and other synthetic androgen such as 7-methylnortestosterone (" MENT ") and acetic ester thereof) (people such as Sundaram, " 7Alpha-Methyl-Nortestosterone (MENT): The Optimal Androgen ForMale Contraception; " Ann.Med., 25:199-205 (1993) (" Sundaram ")).Owing to relate to AR in male sexual development and function, AR is likely the target spot of the Hormone Replacement Therapy of realizing male contraceptive or other form.

The social consciousness of worldwide population growth and birth control has encouraged people to carry out big quantity research at contraception.Contraception under any circumstance all is a difficult problem.It is full of culture and society branding and religion and involves, and the most definite be remarkably influenced to health.When theme concentrated on male contraceptive, these situations only can be aggravated especially.Although suitable contraceptive device is arranged, in history, society expects that the women shoulders the decision of contraception and the responsibility of its consequence.Though for the health of sexually transmitted disease (STD) is considered to make that the male safe and responsible sexual custom that has recognized the need to more form, women still usually bear the pressure that contraception is selected.The women has many selections, from temporary transient mechanical implement such as sponge and barrier film to temporary transient chemical utensil such as spermicide.The women also has the more persistent selection that arranged by they, as if the physics utensil of IUDs and Diaphragm contraceptive and so on, and such as the more persistent method of chemical treatment of oral contraceptive and hypodermic implant.Yet up to now, the only selection of man comprises uses condom or vasotomy., because minimizing property susceptibility, disruptive is spontaneous and cause pregnant obvious possibility because of breaking or misapply, so, many man's disapproves use condoms.Vasotomy is also agreed with.If the man has the long-acting method that need not prolusion before the contraceptive device more easily, particularly sexual behaviour at once, these class methods can increase the man bears more responsibilities to contraception possibility significantly.

In this regard, give male hormone (for example testosterone and derivative thereof) and demonstrated special hope, this is because these compounds have suppresses gonad-stimulating hormone and substitute androgenic association property (people such as Steinberger, " Effect of Chronic Administration ofTestosterone Enanthate On Sperm Productionand Plasma Testosterone; Follicle Stimulating Hormone; and Luteinizing Hormone Levels:APreliminary Evaluation Of a Possible Male Contraceptive ", Fertility andSterility 28:1320-28 (1977)).Giving the high dosage testosterone for a long time can eliminate sperm generation (no sperm) fully or make oligospermia to the utmost point low-level (oligospermia).The degree that suppresses for the sterile required spermatogeny of generation does not know for sure.Yet, the nearest report of the World Health Organization shows, intramuscularly testosterone heptanoate causes no sperm or serious oligospermia (be every milliliter less than 3,000,000 sperms) and sterile (World Health Organization Task Force On Methods A/RegulationOf Male Fertility in 98% the man who receives treatment weekly, " Contracepttve Efficacy Of Testosterone-InducedAzoospermia and Oligospermia in Normal Men, " Fertility and Sterility65:821-29 (1996)).

Develop absorbed slowlyer various testosterone esters after the intramuscularly, thereby caused the effect of stronger short male property.In these esters, being most widely used of testosterone heptanoate.Though it is valuable that the testosterone heptanoate is used in foundation aspect the feasibility of hormone drug of male contraceptive, but it has some defectives, comprise the testosterone levels (Wu that need inject and exist the excusing from death reason peak that occurs immediately after the intramuscularly weekly, " Effects Of TestosteroneEnanthate in Normal Men:Experience From a Multicenter ContraceptiveEfficacy Study, " Fertility and Sterility 65:626-36 (1996))

Can be in conjunction with AR and as male sex hormone (for example testosterone heptanoate) or for many years known as the steroid part of androgen antagonist (for example cyproterone acetate), and use (Wu1988) clinically.Although the on-steroidal androgen antagonist is used for the hormonal dependent prostate cancer clinically,, still there is not the androgenic report of on-steroidal.Therefore, the research to male contraceptive mainly concentrates on the sterid.

Prostate cancer is one of the most recurrent cancer of the U.S. male sex, annual newly-increased hundreds of thousands of diagnosed SARS case.Unfortunately, surpass that 60% new diagnosed SARS case can't be treated and be to be in prognosis bad pathology late period.A kind of method that addresses this problem is to find earlier that by screening procedure (screening programs) prostate cancer also reduces advanced prostate cancer patient's number thus.Yet another strategy is the medicine of development prevention prostate cancer.1/3rd surpass 50 years old man has latent prostate cancer form, and it may activate and become life-threatening clinical prostate cancer form.Shown that latent tumor of prostate occurrence frequency was all increasing from 50 years old (5.3-14%) to 90 years old (40-80%) substantially in per ten years basically.Between literate, nationality and the race number of latent prostate cancer be identical, yet it is significantly different to have the occurrence frequency of aggressive cancer clinically.So just can suppose that environmental factors may play effect in activating the latent prostate cancer.Therefore, treatment of prostate cancer and preventative strategies can research can have the most comprehensive effect to the treatment prostate cancer on medical science and economics.

Osteoporosis is a kind of skeletal diseases of general, it is characterized in that bone density is hanged down and the degeneration of osseous tissue, and the result has increased the susceptibility of bone friability and fracture.In the U.S., this situation influences 2,500 ten thousand people and causes annual 1300000 people of surpassing fracture, comprises annual 500,000 people's backbones, 250,000 human femurs and 240,000 people's fracture of the carpal bone.Fracture of femur is result the most serious in the osteoporosis, has the patient of 5-20% dead in 1 year, and loses viability above 50% survivor.The elderly suffers from the dangerous maximum of osteoporosis, so this problem is estimated because aging population will significantly promote.Expectation global fracture sickness rate in following 60 years will increase by three times, and a research estimates in the year two thousand fifty 4500000 people's hip fractures to be arranged.

The women has more the danger of suffering from osteoporosis than the man.The women will experience a process of bone loss rapidly in 5 years after menopause.Other factor that increases this danger comprises smoking, excessive drinking, motionless mode of life and the low picked-up of measuring calcium of sitting.Yet osteoporosis also often occurs in male.Verified male bone mineral density reduces with the growth at age.The quantity of bone mineral content and density reduces with the bone strength reduction and is easy to fracture relevant.Molecule mechanism in the pleiotropy effect of non-germinal tissue sexual hormoue only begins to understand, but obviously male sex hormone and estrogenic physiological concentration play an important role to keeping the bone homeostasis in whole life.Therefore, when male sex hormone or oestrogenic hormon were lost, its result had increased the bony remodeling ratio, has made the balance that absorbs and form tend to absorb again, has promoted the total loss of bone amount.Male adult back sexual hormoue natural depletion (male sex hormone and the low-level estrogenic direct decline that is obtained by the aromizing of male sex hormone periphery) is relevant with the fragility of bone.Malely also observed such result what castrate.

Old male male sex hormone reduces the carrying out property minimizing that (ADAM) is meant that male sex hormone produces after the male middle age usually.This syndromes feature is about the change in health and intelligence scope, and can be by the processing of male sex hormone environment is revised.ADAM not only shows as the minimizing of serum androgen on biological chemistry, also show for example minimizing of tethelin, melatonin and dehydroepiandrosterone of other hormone.Clinical manifestation comprises fatigue, dysthymia disorders, sexual desire reduction, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, trichomadesis, obesity, muscle wasting, osteopenia, benign prostatic hyperplasia, anaemia, the variation of mood and insight and prostate cancer.

Female hypoandrogenism (ADIF) refers to various hormone associated conditions after the female middle age usually.This syndromes is characterized as variation, anaemia, dysthymia disorders, anaemia, trichomadesis, obesity, endometriosis, mammary cancer, uterus carcinoma and the ovarian cancer of sexual dysfunction, sexual desire reduction, hypogonadism, muscle wasting, osteopenia, osteoporosis, insight and mood.

Muscle wasting refers to the progressive loss of flesh piece and/or the progressive weakening and the degeneration of muscle, comprises the voluntary muscle of human bones or controls movement, the cardiac muscle and the unstriated muscle of control heart (cardiomyopathics).Chronic muscle wasting is a kind of chronic disease (for example continuing a very long time) that weakens and deteriorate to feature with the progressive loss of flesh piece, muscle.The flesh piece loss that takes place during muscle wasting can show as the muscle protein decomposition or degenerate.Protein degradation is the protein synthesis owing to unusual high speed protein degradation, unusual low rate, or both combinations.Protein is aging, and no matter it is because protein extremely is aging or very few protein synthesis, all can cause the flesh piece to reduce and muscle wasting.Muscle wasting is relevant with chronic, neurological, genetic or infective pathology (pathology), ailing (illness), disease (disease) or related symptoms (condition).These comprise amyotrophy for example pseudohypertrophic amyotrophy and myotonia atrophica; The for example scorching amyotrophy (PPMA) of back marrow cinereum matter of amyotrophy; Emaciation is heart emaciation, AIDS emaciation and cancer cachexia, nutritional trouble, leprosy, diabetes, ephrosis, chronic obstructive pulmonary disease (COPD), cancer, late period renal failure, wind-puff, osteomalacia, HIV infection, AIDS and cardiomyopathy for example, in addition, other environment is relevant with muscle wasting with condition also can cause muscle wasting.These comprise chronic low back pain, advanced age, central nervous system (CNS) damage, peripheral nerve injury, Spinal injury, chemical damage, central nervous system damage, peripheral lesion, spinal cord lesion, chemical damage, burn, when a limb maintain static, because when disease or injured long-term hospital care and uselessly deacclimatizing of taking place of alcoholism with property.If continue not alleviate, muscle wasting can have fearful health consequences.For example, occur in the weakening that variation during the muscle wasting can cause physical state, it is harmful to individual health, causes increasing the susceptibility of physical state of infections, weakness and the susceptibility of injury.

At basic science with press for clinically and adopt new method development compound, be used for a) male contraceptive; B) various relevant treatment of conditions with hormone, for example with old age male male sex hormone reduce relevant disease (ADAM), for example fatigue, dysthymia disorders, sexual desire reduction, sexual dysfunction, erective dysfunction, hypogonadism, osteoporosis, trichomadesis, anaemia, obesity, muscle wasting, osteopenia, osteoporosis, benign prostatic hyperplasia, in the change and the prostate cancer of mood, insight; C) to the treatment of female male sex hormone decline (ADIF) diseases related, for example sexual dysfunction, sexual desire minimizing, hypogonadism, muscle wasting, osteopenia, osteoporosis are to the change of insight and mood, depression, anaemia, alopecia, obesity, endometriosis, mammary cancer, uterus carcinoma and ovarian cancer; D) treating and/or preventing acute and/or chronic muscle wasting disease; E) prevent and/or treat dry eyes illness f) the oral androgenic replacement therapy; G) reduce prostate cancer sickness rate, interrupt or impel the deterioration of prostate cancer; And/or h) apoptosis of inducing cancer cell.

Summary of the invention

In one embodiment, the invention provides androgen receptor target agent (ARTA).What the target agent defined is a new subclass compound of those SARM (SARMs).The androgen antagonist activity of the non-steroidal ligands that androgen receptor modulator compounds had not been expected owing to androgen receptor has.In one embodiment, androgen receptor modulator compounds irreversible fixation androgen receptor.In another embodiment, androgen receptor modulator compounds is an androgen receptor antagonists, and it is irreversibly in conjunction with androgen receptor.In another embodiment, androgen receptor modulator compounds is an alkylating agent.Androgen receptor modulator compounds, or separately or as a kind of composition, they are useful to following situation: a) male contraceptive; B) treatment of various hormone associated conditions, for example with male male sex hormone decline (ADAM) diseases associated, for example fatigue, depression, sexual desire reduction, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, alopecia, anaemia, obesity, muscle wasting, osteopenia, osteoporosis, benign prostatic hyperplasia are in the change and the prostate cancer of mood, insight; C) to the treatment of female male sex hormone decline (ADIF) diseases related, for example sexual dysfunction, sexual desire minimizing, hypogonadism, muscle wasting, osteopenia, osteoporosis are to the change of insight and mood, depression, anaemia, alopecia, obesity, endometriosis, mammary cancer, uterus carcinoma and ovarian cancer; D) treating and/or preventing acute and/or chronic muscle wasting disease; E) prevent and/or treat the dry eyes illness; F) oral androgenic replacement therapy; G) reduce prostate cancer sickness rate, interrupt or impel the deterioration of prostate cancer; And/or h) cancer cell specific induction of apoptosis.

In one embodiment, the invention provides suc as formula SARM (SARM) compound shown in the I structure:

X is a key, O, CH ₂, NH, S, Se, PR, NO or NR;

G is O or S;

T be OH, OR ,-NHCOCH ₃Or NHCOR;

R is alkyl, haloalkyl, dihalo alkyl, tri haloalkyl, CH ₂F, CHF ₂, CF ₃, CF ₂CF ₃, aryl, phenyl, halogen, thiazolinyl or OH;

R ₁Be CH ₃, CH ₂F, CHF ₂, CF ₃, CH ₂CH ₃Or CF ₂CF ₃

R ₂Be F, Cl, Br, I, CH ₃, CF ₃, OH, CN, NO ₂, NHCOCH ₃, NHCOCF ₃, NHCOR, alkyl, aralkyl, OR, NH ₂, NHR, NR ₂, SR;

R ₃Be F, Cl, Br, I, CN, NO ₂, COR, COOH, CONHR, CF ₃, SnR ₃, perhaps R ₃Form the condensed ring system of following structure with the phenyl ring that is connected:

Or

Z is NO ₂, CN, COR, COOH or CONHR;

Y is CF ₃, F, Br, Cl, I, CN or SnR ₃

Q is SCN, NCS, OCN or NCO;

N is the integer of 1-4; With

M is the integer of 1-3.

In another embodiment, the invention provides analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, pharmaceutical preparation, hydrate or the N-oxide compound of the compound of formula I, perhaps their arbitrary combination.

In one embodiment, G is O in the Compound I.In another embodiment, X is O in the Compound I.In another embodiment, T is OH in the Compound I.In another embodiment, R in the Compound I ₁Be CH ₃In another embodiment, Z is NO in the Compound I ₂In another embodiment, Z is CN in the Compound I.In another embodiment, the Y in the Compound I is CF ₃In another embodiment, Q is NCS in the Compound I.In another embodiment, in the Compound I Q in contraposition.In another embodiment, Z is in contraposition in the Compound I.In another embodiment, position between Y is in the Compound I.In another embodiment, G is O in the Compound I, and T is OH, and R is CH ₃, X is O, Z is NO ₂, Y is CF ₃, and Q is NCS.

In another embodiment, the invention provides suc as formula the SARM (SARM) shown in the II structure.

Wherein, X is a key, O, CH ₂, NH, S, Se, PR, NO or NR;

G is O or S;

R ₁Be CH ₃, CH ₂F, CHF ₂, CF ₃, CH ₂CH ₃Or CF ₂CF ₃

T be OH, OR ,-NHCOCH ₃Or NHCOR;

R is alkyl, haloalkyl, dihalo alkyl, tri haloalkyl, CH ₂F, CHF ₂, CF ₃,

CF ₂CF ₃, aryl, phenyl, halogen, thiazolinyl or OH;

A is selected from following ring:

With

B is selected from following ring:

With

Wherein A and B can not be phenyl ring simultaneously;

Z is NO ₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF ₃, F, I, Br, Cl, CNCR ₃Or SnR ₃

Q ₁Be NCS, SCN, NCO or OCN;

Q ₂Be H, alkyl, halogen, CF ₃, CNCR ₃, SnR ₃, NR ₂, NHCOCH ₃, NHCOCF ₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH ₃, NHCSCF ₃, NHCSR, NHSO ₂CH ₃, NHSO ₂R, OR, COR, OCOR, OSO ₂R, SO ₂R, SR,

Q ₃And Q ₄Independently be respectively H, alkyl, halogen, CF ₃, CNCR ₃, SnR ₃, NR ₂, NHCOCH ₃, NHCOCF ₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH ₃, NHCSCF ₃, NHCSR, NHSO ₂CH ₃, NHSO ₂R, OR, COR, OCOR, OSO ₂R, SO ₂R, SR;

W ₁Be O, NH, NR, NO or S; With

W ₂Be N or NO.

In another embodiment, the invention provides analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or the N-oxide compound of the compound of formula II, perhaps their arbitrary combination.

In one embodiment, G is O among the Compound I I.In another embodiment, X is O among the Compound I I.In another embodiment, T is OH among the Compound I I.In another embodiment, R among the Compound I I ₁Be CH ₃In another embodiment, Z is NO among the Compound I I ₂In another embodiment, Z is CN among the Compound I I.In another embodiment, Y is CF among the Compound I I ₃In another embodiment, Q among the Compound I I ₁Be NCS.In another embodiment, Q among the Compound I I ₁Be in contraposition.In another embodiment, Z is in contraposition among the Compound I I.In another embodiment, position between the Y among the Compound I I is in.In another embodiment, the G among the Compound I I is O, and T is OH, and R is CH ₃, X is O, Z is NO ₂, Y is CF ₃, and Q is NCS.

In another embodiment, the invention provides SARM (SARM) shown in the formula III structure.

Wherein, X is a key, O, CH ₂, NH, S, Se, PR, NO or NR;

G is O or S;

T be OH, OR ,-NHCOCH ₃Or NHCOR;

Z is NO ₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF ₃, F, I, Br, Cl, CN, CR ₃Or SnR ₃

Q is SCN, NCS, OCN or NCO;

R is alkyl, haloalkyl, dihalo alkyl, tri haloalkyl, CH ₂F, CHF ₂, CF ₃, CF ₂CF ₃, aryl, phenyl, halogen, thiazolinyl or OH; With

R ₁Be CH ₃, CH ₂F, CHF ₂, CF ₃, CH ₂CH ₃Or CF ₂CF ₃

In another embodiment, the invention provides analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or the N-oxide compound of the compound of formula III, perhaps their arbitrary combination.

In one embodiment, G is O in the compound III.In another embodiment, X is O in the compound III.In another embodiment, T is OH in the compound III.In another embodiment, R in the compound III ₁Be CH ₃In another embodiment, Z is NO in the compound III ₂In another embodiment, Z is CN in the compound III.In another embodiment, Y is CF in the compound III ₃In another embodiment, Q is NCS in the compound III.In another embodiment, Q is in contraposition in the compound III.In another embodiment, Z is in contraposition in the compound III.In another embodiment, Y is in a contraposition in the compound III.In another embodiment, G is O in the compound III, and T is OH, R ₁Be CH ₃, X is O, Z is NO ₂, Y is CF ₃, and Q is NCS.

In another embodiment, the invention provides suc as formula the SARM (SARM) shown in the IV structure.

Wherein, X is a key, O, CH ₂, NH, S, Se, PR, NO or NR;

Z is NO ₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF ₃, F, I, Br, Cl, CN, CR ₃Or SnR ₃

Q is SCN, NCS, OCN or NCO; With

R is alkyl, haloalkyl, dihalo alkyl, tri haloalkyl, CH ₂F, CHF ₂, CF ₃, CF ₂CF ₃, aryl, phenyl, halogen, thiazolinyl or OH.

In another embodiment, the invention provides analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or the N-oxide compound of the compound of formula IV, perhaps their arbitrary combination.

In one embodiment, X is O in the compound IV.In another embodiment, Z is NO in the compound IV ₂In another embodiment, Z is CN in the compound IV.In another embodiment, Y is CF in the compound III ₃In another embodiment, Q is NCS in the compound III.

In another embodiment, the invention provides SARM (SARM) shown in a kind of formula V structure, and/or analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination.

In one embodiment, arbitrary androgen receptor modulator compounds of representing of formula I-V is an androgen receptor antagonists.In another embodiment, arbitrary androgen receptor modulator compounds of representing of formula I-V is irreversibly in conjunction with androgen receptor.In another embodiment, arbitrary androgen receptor modulator compounds that combined type I-V represents is an androgen receptor antagonists, and it is irreversibly in conjunction with androgen receptor.In another embodiment, arbitrary androgen receptor modulator compounds of representing of formula I-V is an alkylating agent.

In one embodiment, the invention provides a kind of SARM compound and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps composition of their arbitrary combination that arbitrary formula I-V represents that comprise.

In another embodiment, the invention provides a kind of SARM compound and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination that arbitrary formula I-V represents that comprise; And the medicinal compositions of appropriate carriers or thinner.

In one embodiment, the present invention further provides a kind of with the method for SARM compound in conjunction with androgen receptor, it may further comprise the steps: be enough to SARM compound and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or the N-oxide compound that the amount in conjunction with androgen receptor is represented arbitrary formula I-V with the SARM compound, perhaps their arbitrary combination contacts with androgen receptor.

In another embodiment, the present invention further provides a kind of with the SARM compound irreversibly in conjunction with the method for androgen receptor, it may further comprise the steps: be enough to irreversibly SARM compound and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or the N-oxide compound that the amount in conjunction with androgen receptor is represented arbitrary formula I-V with the SARM compound, perhaps their arbitrary combination contacts with androgen receptor.

In another embodiment, the present invention further provides the alkylating method of a kind of androgen receptor, it may further comprise the steps: the SARM compound and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or the N-oxide compound that arbitrary formula I-V are represented with the amount of effective alkylation androgen receptor, perhaps their arbitrary combination contacts with androgen receptor.

In another embodiment, the invention provides a kind of spermatogenetic method that in patient's body, suppresses, it may further comprise the steps: SARM compound and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound that the amount that produces with effective inhibition sperm is represented arbitrary formula I-V, perhaps their arbitrary combination contacts with androgen receptor.

In another embodiment, the invention provides a kind of in the male patient body method of contraception, it may further comprise the steps: with the amount that effective inhibition sperm produces the patient is used SARM compound and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or the N-oxide compound that arbitrary formula I-V represents, perhaps their arbitrary combination causes the effect of practising contraception thus in patient's body.

In another embodiment, the present invention further provides a kind of method of hormonotherapy, it may further comprise the steps: the SARM compound and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or the N-oxide compound that effectively in conjunction with androgen receptor bonded amount arbitrary formula I-V are represented with the SARM compound, perhaps their arbitrary combination contacts with androgen receptor, relies on the effect that illness changes to reach male sex hormone.

In another embodiment, the invention provides a kind of method of hormone replacement therapy, it may further comprise the steps: with SARM compound and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound that the significant quantity that effectively causes the change of male sex hormone dependence illness is represented arbitrary formula I-V, perhaps their arbitrary combination contacts with patient's androgen receptor.

In another embodiment, the present invention provides a kind of treatment to have hormone associated conditions patient's method in addition, it may further comprise the steps: effectively in conjunction with the amount of androgen receptor the patient is used SARM compound and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or the N-oxide compound that arbitrary formula I-V represents, perhaps their arbitrary combination changes the effect that male sex hormone relies on illness to reach.

In another embodiment, the present invention further provides a kind of method for the treatment of the carcinoma of prostate patient, it may further comprise the steps: the amount with effective treatment carcinoma of prostate patient is used SARM compound and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination that arbitrary formula I-V represents to the patient.

In another embodiment, the invention provides a kind of method of preventing the carcinoma of prostate patient, it may further comprise the steps: the amount with effective treatment carcinoma of prostate patient is used SARM compound and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination that arbitrary formula I-V represents to the patient.

In another embodiment, the present invention further provides a kind of delay and suffer from the method for patients with prostate cancer prostate cancer progress, it may further comprise the steps: the amount with effective delay patient's prostate cancer disease progress is used SARM compound and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination that arbitrary formula I-V represents to the patient.

In another embodiment, the present invention further provides a kind of prevention and suffer from the method for patients with prostate cancer prostate cancer recurrence, it may further comprise the steps: the amount with effective prevention patient's prostate cancer recurrence is used SARM compound and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination that arbitrary formula I-V represents to the patient.

In another embodiment, the invention provides a kind of method for the treatment of the recurrence of carcinoma of prostate patient's prostate cancer, it may further comprise the steps: the amount with effective treatment patient's prostate cancer recurrence is used SARM compound and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination that arbitrary formula I-V represents to the patient.

In another embodiment, the invention provides a kind of method for the treatment of dry eye patients dry eyes illness, it may further comprise the steps: the amount with effective treatment patient dry eyes is used SARM compound and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination that arbitrary formula I-V represents to the patient.

In another embodiment, the invention provides a kind of method of preventing dry eye patients dry eyes illness, it may further comprise the steps: the amount with effective prevention patient dry eyes is used SARM compound and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination that arbitrary formula I-V represents to the patient.

In another embodiment, the invention provides a kind of method of inducing the prostate cancer cell apoptosis, it may further comprise the steps: with the amount of effectively inducing the prostate cancer cell apoptosis patient is used SARM compound and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination that arbitrary formula I-V represents.

In another embodiment, the invention provides the preparation method of SARM (SARM) compound shown in a kind of formula I structure:

Wherein X is O, NH, S, Se, PR or NR;

G is O or S;

T be OH, OR ,-NHCOCH ₃Or NHCOR;

R ₁Be CH ₃, CH ₂F, CHF ₂, CF ₃, CH ₂CH ₃Or CF ₂CF ₃

R ₃Be F, Cl, Br, I, CN, NO ₂, COR, COOH, CONHR, CF ₃, SnR ₃, perhaps

R ₃Form the condensed ring system of following structure with the phenyl ring that is connected:

Or

Z is NO ₂, CN, COR, COOH or CONHR;

Y is CF ₃, F, Br, Cl, I, CN or SnR ₃

Q is SCN, NCS, OCN or NCO;

N is the integer of 1-4; With

M is the integer of 1-3.

Method comprises the compound of formula VIII:

Wherein Z, Y, G, R ₁, T, R ₃With m such as above-mentioned definition and L be leavings group, with the compound link coupled step of formula IX,

Q wherein,, X, R ₂With n such as above-mentioned definition.

In one embodiment, coupling step carries out in the presence of alkali.In another embodiment, leavings group L is Br.In another embodiment, formula VIII compound is as follows:

I) by formula XI ring compound open loop preparation formula X compound

Wherein L, R ₁, G and T as above define, and T ₁Be O or NH; With

The ii) amine of formula XII

Wherein Z, Y, R ₃As above define with m, in the presence of coupling agent with formula X compound

Reaction is with preparation formula VIII compound.

In one embodiment, step (a) is reacted in the presence of HBr.In another embodiment, present method further comprises the step that SARM (SARM) compound is converted to its analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, hydrate or their arbitrary combination.

In another embodiment, the invention provides the preparation method of the SARM (SARM) shown in the preparation formula II structure.

Wherein, X is O, NH, S, Se, PR or NR;

G is O or S;

R ₁Be CH ₃, CH ₂F, CHF ₂, CF ₃, CH ₂CH ₃Or CF ₂CF ₃

T be OH, OR ,-NHCOCH ₃Or NHCOR;

A is selected from following ring compound:

With

B is selected from following ring compound:

With

Wherein A and B can not be phenyl ring simultaneously;

Z is NO ₂, CN, COOH, COR, NHCOR, CONHR;

Y is CF ₃, F, I, Br, Cl, CN, CR ₃Or SnR ₃

Q ₁Be NCS, SCN, NCO or OCN;

Q ₃And Q ₄Independently be H, alkyl, halogen, CF separately ₃, CNCR ₃, SnR ₃, NR ₂, NHCOCH ₃, NHCOCF ₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH ₃, NHCSCF ₃, NHCSR, NHSO ₂CH ₃, OR, COR, OCOR, OSO ₂R, SO ₂R or SR;

W ₁Be O, NH, NR, NO or S; With

W ₂Be N or NO;

This method comprises formula XIII compound

Wherein A, G, RI and T as above define, and L is leavings group,

With HX-B compound link coupled step, wherein B and X as above define.

In one embodiment, coupling step carries out in the presence of alkali.In another embodiment, leavings group L is Br.In another embodiment, formula XIII compound is as follows:

I) by the compound of formula XI ring compound open loop preparation formula X

Wherein L, R ₁, G and T as above define, and T ₁Be O or NH; With

Ii) formula A-NH ₂Amine, wherein A as above defines, in the presence of coupling agent, with the step of formula X compound reaction, with the amine of preparation formula XIII.

In one embodiment, step (a) is reacted in the presence of HBr.In another embodiment, present method further comprises the step that SARM (SARM) compound is transformed into its analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, hydrate or their arbitrary combination.

In another embodiment, the invention provides a kind of preparation method by SARM (SARM) compound shown in the formula III structure:

Wherein X is O, NH, S, Se, PR or NR;

G is O or S;

T be OH, OR ,-NHCOCH ₃Or NHCOR;

Z is NO ₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF ₃, F, I, Br, Cl, CN, CR ₃Or SnR ₃

Q is SCN, NCS, OCN or NCO;

R ₁Be CH ₃, CH ₂F, CHF ₂, CF ₃, CH ₂CH ₃Or CF ₂CF ₃

This method comprises formula XIV compound:

Wherein Z, Y, G, R1 and T as above define and L is a leavings group, and the coupling step of formula XV compound:

Wherein Q and X as above define.

In one embodiment, coupling step carries out in the presence of alkali.In another embodiment, leavings group L is Br.In another embodiment, formula XIII compound is by following preparation:

I) by the compound of formula XI ring compound open loop preparation formula X

Wherein L, R1, G and T as above define, and G is O, and T ₁Be O or NH; With

The ii) amine of formula XVI

The step of reacting with formula X compound in the presence of coupling agent is to generate compounds X IV

In one embodiment, step (a) is reacted in the presence of HBr.In another embodiment, present method comprises that further SARM (SARM) compound is transformed into the step of its analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, hydrate or their arbitrary combination.

In another embodiment, the invention provides a kind of preparation method by SARM (SARM) compound shown in the formula IV structure:

Wherein X is O, NH, S, Se, PR or NR;

Z is NO ₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF ₃, F, I, Br, Cl, CN, CR ₃Or SnR ₃

Q is SCN, NCS, OCN or NCO; With

This method comprises formula XVII compound

Wherein Z, Y, G, R and T as above define and L is a leavings group, and the coupling step of formula XVIII compound:

Wherein Q and XR ₂As above definition.

In one embodiment, coupling step carries out in the presence of alkali.In another embodiment, leavings group L is Br.In another embodiment, formula XVII compound is by following preparation:

I) by the compound of formula XI ring compound open loop preparation formula X

Wherein L, R ₁, G and T as above define, and T ₁Be O or NH; With

The ii) amine of formula XVIX

In the presence of coupling agent with the step of formula X compound, with preparation compounds X VII

In one embodiment, step (a) is reacted in the presence of HBr.In another embodiment, present method further comprises the step of the mixture purification androgen receptor modulator compounds that uses the second alcohol and water.In another embodiment, present method further comprises the step that SARM (SARM) compound is converted into its analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, hydrate or their arbitrary combination.

The SARM compound that the present invention is new, independent or a kind of pharmaceutical composition has following purposes: a) male contraceptive; B) Zhi Liao various hormone associated conditions, for example relevant with ADAM illness is such as fatigue, depression, sexual desire minimizing, sexual dysfunction, hypogonadism, osteoporosis, alopecia, anaemia, obesity, muscle wasting, osteopenia, osteoporosis, benign prostatic hyperplasia, in the change and the prostate cancer of mood, insight; C) to the treatment of female male sex hormone decline (ADIF) diseases related, for example sexual dysfunction, sexual desire minimizing, hypogonadism, muscle wasting, osteopenia, osteoporosis are to the change of insight and mood, depression, anaemia, alopecia, obesity, endometriosis, mammary cancer, uterus carcinoma and ovarian cancer; D) treating and/or preventing acute and/or chronic muscle wasting disease; E) prevent and/or treat the dry eyes illness; F) oral androgenic replacement therapy; G) reduce prostate cancer sickness rate, interrupt or impel the deterioration of prostate cancer; And/or h) cancer cell specific induction of apoptosis.

Because SARM compound of the present invention has shown to have short male property effect in vivo, and androgen receptor is had the anabolic activity of on-steroidal part, and SARM compound of the present invention provides a kind of important improvement to the steroid androgenotherapy.Therefore, the SARM compound has the anabolic activity of short male property effect and on-steroidal androgen receptor part, and the method for application or expensive that does not have severe side effect, inconvenience, and still have good oral bioavailability, do not have and other steroid receptor cross reactivities, and long biological half-life.

The accompanying drawing summary

From following be included in detailed description that accompanying drawing combines go to understand and understand the present invention more fully:

Fig. 1: the cytotoxicity of androgen receptor modulator compounds in different clone.

A) compound V; B) S-NTBA; C) R-CTF-T-CA-1; And D) R-CTF-T-BA-1.

Fig. 2: the cytotoxicity (24 hour and 6 day handle) of androgen receptor modulator compounds in prostate cancer cell line.A)R-CTF-T-BA-1；B)R-CTF-T-CA-1；

C) S-NTBA; And D) compound V.

Fig. 3: the cytotoxicity (24 hour and 6 day handle) of androgen receptor modulator compounds in CV-1 control cells system.A)R-CTF-T-BA-1；B)R-CTF-T-CA-1；

C) S-NTBA; And D) compound V.

Fig. 4: the cytotoxicity (24 hour and 6 day handle) of androgen receptor modulator compounds in PC-3 bone metastatic prostate cancer clone.A) R-CTF-T-BA-1; B) R-CTF-T-CA-1; C) S-NTBA; And D) 5 FU 5 fluorouracil.

Detailed Description Of The Invention

In one embodiment, the invention provides androgen receptor target agent (ARTA).What the target agent defined is a new subclass compound of those SARM (SARMs).Androgen receptor modulator compounds has the androgen antagonist activity of the non-steroidal ligands of beyong contemplation owing to androgen receptor.In one embodiment, androgen receptor modulator compounds is irreversible in conjunction with androgen receptor.In another embodiment, androgen receptor modulator compounds is an androgen receptor antagonists, and it is irreversible in conjunction with androgen receptor.In another embodiment, androgen receptor modulator compounds is an alkylating agent.Androgen receptor modulator compounds, independent or work is a kind of composition, they are useful to following situation: a) male contraceptive; B) treatment of various hormone associated conditions, for example with male male sex hormone decline (ADAM) diseases associated, for example fatigue, depression, sexual desire reduction, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, alopecia, anaemia, obesity, muscle wasting, osteopenia, osteoporosis, benign prostatic hyperplasia are in the change and the prostate cancer of mood, insight; C) to the treatment of female male sex hormone decline (ADIF) diseases related, for example sexual dysfunction, sexual desire minimizing, hypogonadism, muscle wasting, osteopenia, osteoporosis are to the change of insight and mood, depression, anaemia, alopecia, obesity, endometriosis, mammary cancer, uterus carcinoma and ovarian cancer; D) treating and/or preventing acute and/or chronic muscle wasting disease; E) prevent and/or treat the dry eyes illness; F) oral androgenic replacement therapy; G) reduce prostate cancer sickness rate, interrupt or impel the deterioration of prostate cancer; And/or h) cancer cell specific induction of apoptosis.

In one embodiment, the invention provides by SARM (SARM) compound shown in the formula I structure:

X is a key, O, CH ₂, NH, S, Se, PR, NO or NR;

G is O or S;

T be OH, OR ,-NHCOCH ₃Or NHCOR;

R ₁Be CH ₃, CH ₂F, CHF ₂, CF ₃, CH ₂CH ₃Or CF ₂CF ₃

R ₃Be F, Cl, Br, I, CN, NO ₂, COR, COOH, CONHR, CF ₃, SnR ₃Perhaps R ₃Form the condensed ring system of following structure with the phenyl ring that is connected:

Or

Z is NO ₂, CN, COR, COOH or CONHR;

Y is CF ₃, F, Br, Cl, I, CN or SnR ₃

Q is SCN, NCS, OCN or NCO;

N is the integer of 1-4; With

M is the integer of 1-3.

In one embodiment, the invention provides the analogue of the compound of formula I.In another embodiment, the invention provides the derivative of the compound of formula I.In another embodiment, the invention provides the isomer of the compound of formula I.In another embodiment, the invention provides the metabolite of the compound of formula I.In another embodiment, the invention provides the pharmacologically acceptable salts of the compound of formula I.In another embodiment, the invention provides the medicament production of the compound of formula I.In another embodiment, the invention provides the hydrate of the compound of formula I.In another embodiment, the invention provides the N-oxide compound of the compound of formula I.In another embodiment, the invention provides any one combination in analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or the N-oxide compound of the compound of formula I.

In one embodiment, G is O in the Compound I.In another embodiment, X is O in the Compound I.In another embodiment, T is OH in the Compound I.In another embodiment, R in the Compound I ₁Be CH ₃In another embodiment, Z is NO in the Compound I ₂In another embodiment, Z is CN in the Compound I.In another embodiment, Y is CF in the Compound I ₃In another embodiment, Q is NCS in the Compound I.In another embodiment, Q is positioned at contraposition in the Compound I.In another embodiment, Z is positioned at contraposition in the Compound I.In another embodiment, position between Y is positioned in the Compound I.In another embodiment, G is O in the Compound I, and T is OH, and R is CH ₃, X is O, Z is NO ₂, Y is CF ₃, and Q is NCS.

In another embodiment, the invention provides the SARM (SARM) that formula II structure is represented:

Wherein, X is a key, O, CH ₂, NH, S, Se, PR, NO or NR;

G is O or S;

R ₁Be CH ₃, CH ₂F, CHF ₂, CF ₃, CH ₂CH ₃Or CF ₂CF ₃

T be OH, OR ,-NHCOCH ₃Or NHCOR;

A is selected from following ring:

With

B is selected from following ring:

With

Wherein A and B can not be phenyl ring simultaneously;

Z is NO ₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF ₃, F, I, Br, Cl, CN CR ₃Or SnR ₃

Q ₁Be NCS, SCN, NCO or OCN;

Q ₂Be H, alkyl, halogen, CF ₃, CNCR ₃, SnR ₃, NR ₂, NHCOCH ₃, NHCOCF ₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH ₃, NHCSCF ₃, NHCSR NHSO ₂CH ₃, NHSO ₂R, OR, COR, OCOR, OSO ₂R, SO ₂R, SR,

Q ₃And Q ₄Independently be respectively H, alkyl, halogen, CF ₃, CNCR ₃, SnR ₃, NR ₂, NHCOCH ₃, NHCOCF ₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH ₃, NHCSCF ₃, NHCSR NHSO ₂CH ₃, NHSO ₂R, OR, COR, OCOR, OSO ₂R, SO ₂R, SR;

W ₁Be O, NH, NR, NO or S; With

W ₂Be N or NO.

In one embodiment, the invention provides the analogue of formula II compound.In another embodiment, the invention provides the derivative of the compound of formula II.In another embodiment, the invention provides the isomer of the compound of formula II.In another embodiment, the invention provides the metabolite of the compound of formula II.In another embodiment, the invention provides the pharmacologically acceptable salts of the compound of formula II.In another embodiment, the invention provides the medicament production of the compound of formula II.In another embodiment, the invention provides the hydrate of the compound of formula II.In another embodiment, the invention provides the N-oxide compound of the compound of formula II.In another embodiment, the invention provides any one combination in analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or the N-oxide compound of the compound of formula II.In one embodiment, G is O among the Compound I I.In another embodiment, X is O among the Compound I I.In another embodiment, T is OH among the Compound I I.In another embodiment, R among the Compound I I ₁Be CH ₃In another embodiment, Z is NO among the Compound I I ₂In another embodiment, Z is CN among the Compound I I.In another embodiment, Y is CF among the Compound I I ₃In another embodiment, Q is NCS among the Compound I I.In another embodiment, Q is positioned at contraposition among the Compound I I.In another embodiment, Z is positioned at contraposition in the Compound I.In another embodiment, position between Y is positioned among the Compound I I.In another embodiment, G is O among the Compound I I, and T is OH, and R is CH ₃, X is O, Z is NO ₂, Y is CF ₃, and Q is NCS.

In another embodiment, the invention provides the SARM shown in the formula III structure (SARM):

Wherein, X is a key, O, CH ₂, NH, S, Se, PR, NO or NR;

G is O or S;

T be OH, OR ,-NHCOCH ₃Or NHCOR;

Z is NO ₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF ₃, F, I, Br, Cl, CN, CR ₃Or SnR ₃

Q is SCN, NCS, OCN or NCO;

R ₁Be CH ₃, CH ₂F, CHF ₂, CF ₃, CH ₂CH ₃Or CF ₂CF ₃

In one embodiment, the invention provides the analogue of the compound of formula III.In another embodiment, the invention provides the derivative of the compound of formula III.In another embodiment, the invention provides the isomer of the compound of formula III.In another embodiment, the invention provides the metabolite of the compound of formula III.In another embodiment, the invention provides the pharmacologically acceptable salts of the compound of formula III.In another embodiment, the invention provides the medicament production of the compound of formula III.In another embodiment, the invention provides the hydrate of the compound of formula III.In another embodiment, the invention provides the N-oxide compound of the compound of formula III.In another embodiment, the invention provides any one combination in analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or the N-oxide compound of the compound of formula III.

In one embodiment, G is O in the compound III.In another embodiment, X is O in the compound III.In another embodiment, T is OH in the compound III.In another embodiment, R in the compound III ₁Be CH ₃In another embodiment, Z is NO in the compound III ₂In another embodiment, Z is CN in the compound III.In another embodiment, Y is CF in the compound III ₃In another embodiment, Q is NCS in the compound III.In another embodiment, Q is in contraposition in the compound III.In another embodiment, Z is in contraposition in the compound III.In another embodiment, position between Y is in the compound III.In another embodiment, G is O in the compound III, and T is OH, R ₁Be CH ₃, X is O, Z is NO ₂, Y is CF ₃, and Q is NCS.

In another embodiment, the invention provides suc as formula the SARM (SARM) shown in the IV structure:

Wherein, X is a key, O, CH ₂, NH, S, Se, PR, NO or NR;

Z is NO ₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF ₃, F, I, Br, Cl, CN, CR ₃Or SnR ₃

Q is SCN, NCS, OCN or NCO; With

In one embodiment, the invention provides the analogue of the compound of formula IV.In another embodiment, the invention provides the derivative of the compound of formula IV.In another embodiment, the invention provides the isomer of the compound of formula IV.In another embodiment, the invention provides the metabolite of the compound of formula IV.In another embodiment, the invention provides the pharmacologically acceptable salts of the compound of formula IV.In another embodiment, the invention provides the medicament production of the compound of formula IV.In another embodiment, the invention provides the hydrate of the compound of formula IV.In another embodiment, the invention provides the N-oxide compound of the compound of formula IV.In another embodiment, the invention provides any one combination in analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or the N-oxide compound of the compound of formula IV.

In another embodiment, the invention provides SARM (SARM) shown in a kind of formula V structure:

In one embodiment, the invention provides the analogue of the compound of formula V.In another embodiment, the invention provides the derivative of the compound of formula V.In another embodiment, the invention provides the isomer of the compound of formula V.In another embodiment, the invention provides the metabolite of the compound of formula V.In another embodiment, the invention provides the pharmacologically acceptable salts of the compound of formula V.In another embodiment, the invention provides the medicament production of the compound of formula V.In another embodiment, the invention provides the hydrate of the compound of formula V.In another embodiment, the invention provides the N-oxide compound of the compound of formula V.In another embodiment, the invention provides any one combination in analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or the N-oxide compound of the compound of formula V.

Expect that as this paper other specific embodiments that comprises in the scope of the invention is compound VI and VII.Comprise any one the combination in analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or the N-oxide compound in the scope of the invention.

Wherein Q is NCS, SCN, NCO or OCN.

The substituting group definition of this paper institute is haloalkyl, dihalo alkyl, tri haloalkyl, CH ₂F, CHF ₂, CF ₃, CF ₂CF ₃, aryl, phenyl, halogen, thiazolinyl or hydroxyl (OH).

" alkyl " refers to aliphatic saturated hydrocarbon, comprises straight chain, side chain and cycloalkyl.In one embodiment, alkyl has the 1-12 carbon atom.In another embodiment, alkyl has the 1-7 carbon atom.In another embodiment, alkyl has the 1-6 carbon atom.In another embodiment, alkyl has the 1-4 carbon atom.Alkyl may be not replace or replaced by one or more halogen, hydroxyl, carbalkoxy, amide group, alkylamidoalkyl, dialkyl amide base, nitro, amino, alkylamino, dialkylamino, carbonyl, sulfo-and alkylthio of being selected from.

" alkylhalide group " refers to alkyl as defined above, and it is replaced by one or more halogen atoms such as F, Cl, Br or I.

" aryl " refers to and contains at least one isocyclic aromatic base or heterocyclic aromatic base, and it is replaced by one or more halogen, alkylhalide group, hydroxyl, carbalkoxy, amide group, alkylamidoalkyl, dialkyl amide base, nitro, amino, alkylamino, dialkylamino, carbonyl, sulfo-or alkylthio of being selected from.The non-limitative example of aromatic ring is phenyl, naphthyl, pyranyl, pyrryl, pyrazinyl, pyrimidyl, pyrazolyl, pyridyl, furyl, sulfur phenenyl, thiazolyl, imidazolyl, isoxazolyl or the like.

" hydroxyl " refers to the OH base." thiazolinyl " refers to and contains a carbon-carbon double bond at least.Halogen refers to F, Cl, Br or I.

" aralkyl " refers to the alkyl that is keyed to aryl, and wherein alkyl and aryl as above define.An example of aralkyl is a phenmethyl.

Expect as this paper, the present invention relates to any one the purposes of combination in androgen receptor modulator compounds and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or the N-oxide compound.In one embodiment, the invention provides the analogue of androgen receptor modulator compounds.In another embodiment, the invention provides the derivative of androgen receptor modulator compounds.In another embodiment, the invention provides the isomer of androgen receptor modulator compounds.In another embodiment, the invention provides the metabolite of androgen receptor modulator compounds.In another embodiment, the invention provides the pharmacologically acceptable salts of the compound of formula I.In another embodiment, the invention provides the medicament production of androgen receptor modulator compounds.In another embodiment, the invention provides the hydrate of androgen receptor modulator compounds.In another embodiment, the invention provides the N-oxide compound of androgen receptor modulator compounds.In another embodiment, the invention provides any one combination in analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or the N-oxide compound of androgen receptor modulator compounds.

As defined herein, term " isomer " includes but not limited to optical isomer and analogue, constitutional isomer and analogue, conformer and analogue or the like.

In one embodiment, the present invention comprises the purposes of the various isomer of androgen receptor modulator compounds.Those skilled in the art understand androgen receptor modifier of the present invention and comprise at least one chiral centre.Therefore, the androgen receptor modifier in the inventive method may exist with form optical optical rotation or racemic.Some compounds may also show polymorphism.The present invention can be understood as and comprises type opticity on racemic arbitrarily, the optics, pantomorphic or steric isomer, or its mixture, and its type has useful characteristic to the treatment of male sex hormone associated conditions described herein.In another embodiment, androgen receptor modifier is single (S)-isomer.In another embodiment, androgen receptor modifier is to comprise (R) of equal amts and (S) racemic mixture of isomer.How well-known this area prepares the form (for example, by the recrystallization technology resolution of racemates, use optics optically-active starting raw material synthetic, use chiral stationary phase to carry out the synthetic or chromatographic separation of chirality) of optical optical rotation.

The present invention includes the amino substitution compound pharmacy acceptable salt of machine or mineral acid such as citric acid and hydrochloric acid.The present invention also comprises the N-oxide compound of amino substituting group compound described herein.Prepare pharmacy acceptable salt with mineral alkali such as sodium-hydroxide treatment phenolic compound.Also can prepare phenolic ester with aliphatics and aromatic carboxylic acid such as acetate and benzoic ether.

The present invention further comprises the derivative of androgen receptor modulator compounds.Term " derivative " includes but not limited to ether derivant, acid derivative, amide derivatives, ester derivative or the like.In addition, the present invention further comprises the hydrate of androgen receptor modulator compounds.Term " hydrate " includes but not limited to semihydrate, monohydrate, trihydrate or the like.

The present invention further comprises the androgen receptor modulator compounds metabolite.Term " metabolite " refers to any material that is produced from another material by metabolism or metabolic process.

The present invention further comprises the androgen receptor modulator compounds medicament production.Term " medicament production " refers to and is suitable for the composition that pharmacy is used (pharmaceutical composition) as herein defined.

In another embodiment, the invention provides the method for preparation SARM of the present invention (SARM) compound.

Method of the present invention is suitable for mass preparation, because all steps produce high-purity compound, so avoided the complicated purification program of final reduction productive rate.Thereby the invention provides the synthetic method of the agonist compound of on-steroidal, it is large-scale synthetic that it can be used for industry, and high yield, highly purified product are provided simultaneously.

In one embodiment, the invention provides preparation method by SARM (SARM) compound shown in the formula I structure:

Wherein X is O, NH, S, Se, PR or NR;

G is O or S;

T be OH, OR ,-NHCOCH ₃Or NHCOR;

R ₁Be CH ₃, CH ₂F, CHF ₂, CF ₃, CH ₂CH ₃Or CF ₂CF ₃

Or

Z is NO ₂, CN, COR, COOH or CONHR;

Y is CF ₃, F, Br, Cl, I, CN or SnR ₃

Q is SCN, NCS, OCN or NCO;

N is the integer of 1-4; With

M is the integer of 1-3.

Method comprises formula VIII compound:

Wherein Z, Y, G, R1, T, R ₃As above define with m, L is a kind of leavings group, with the coupling step of formula IX compound

Wherein Q, X, R ₂As above define with n.

I) by the compound of formula XI ring compound open loop preparation formula X

Wherein L, R1, G and T as above define, and T ₁Be O or NH; With

The ii) amine of formula XII

Wherein Z, Y, R ₃As above define with m, in the presence of coupling agent, react, with preparation formula VIII compound with formula X compound.

In one embodiment, step (a) is reacted in the presence of HBr.In another embodiment, present method further comprises the step that SARM (SARM) compound is changed into its analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, hydrate or their arbitrary combination.

In another embodiment, the invention provides preparation method suc as formula the SARM (SARM) shown in the II structure:

Wherein, X is O, NH, S, Se, PR or NR;

G is O or S;

R ₁Be CH ₃, CH ₂F, CHF ₂, CF ₃, CH ₂CH ₃Or CF ₂CF ₃

T be OH, OR ,-NHCOCH ₃Or NHCOR;

A is selected from following ring compound:

With

B is selected from following ring compound:

With

Wherein A and B can not be phenyl ring simultaneously;

Z is NO ₂, CN, COOH, COR, NHCOR, CONHR;

Y is CF ₃, F, I, Br, Cl, CN, CR ₃Or SnR ₃

Q ₁Be NCS, SCN, NCO or OCN;

Q ₃And Q ₄Independently be H, alkyl, halogen, CF separately ₃, CNCR ₃, SnR ₃, NR ₂, NHCOCH ₃, NHCOCF ₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH ₃, NHCSCF ₃, NHCSRNHSO ₂CH ₃, NHCOOR, OR, COR, OCOR, OSO ₂R, SO ₂R or SR;

W ₁Be O, NH, NR, NO or S; With

W ₂Be N or NO;

This step comprises formula XIII compound:

Wherein A, G, R ₁As above define with T, and L is leavings group,

With the coupling step of formula HX-B compound, wherein B and X as above define.

I) by the compound of formula XI ring compound open loop preparation formula X

Wherein L, R ₁, G and T as above define, and T ₁Be O or NH; With

Ii) formula A-NH ₂Amine, wherein A as above defines, in the presence of coupling agent with formula X compound reaction, with preparation formula XIII compound.

In another embodiment, the invention provides the preparation method of the SARM (SARM) shown in the formula III structure:

Wherein, X is O, NH, S, Se, PR or NR;

G is O or S;

T be OH, OR ,-NHCOCH ₃Or NHCOR;

Z is NO ₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF ₃, F, I, Br, Cl, CN, CR ₃Or SnR ₃

Q is SCN, NCS, OCN or NCO;

R ₁Be CH ₃, CH ₂F, CHF ₂, CF ₃, CH ₂CH ₃Or CF ₂CF ₃

Method comprises that formula is with formula XIV compound:

Wherein Z, Y, G, R ₁, T as above defines, L is a kind of leavings group, and the coupling step of formula XV compound:

Wherein Q, X as above define.

In one embodiment, coupling step carries out in the presence of alkali.In another embodiment, leavings group L is Br.In another embodiment, formula XIV compound is as follows:

I) by the compound of formula XI ring compound open loop preparation formula X

Wherein L, R ₁, G and T as above define, G is O, and T ₁Be O or NH; With

The ii) amine of formula XVI

In the presence of coupling agent with the reaction of formula X compound, with preparation formula XIII compound.

Wherein, X is O, NH, S, Se, PR or NR;

Z is NO ₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF ₃, F, I, Br, Cl, CN, CR ₃Or SnR ₃

Q is SCN, NCS, OCN or NCO; With

Method comprises formula XVII amine:

Wherein Z, Y as above define, and L is a kind of leavings group, and the coupling step of formula XVIII compound:

Wherein Q, X R ₂As above definition.

In one embodiment, coupling step carries out in the presence of alkali.In another embodiment, leavings group L is Br.In another embodiment, formula XVII compound is as follows:

I) by the compound of formula XI ring compound open loop preparation formula X

Wherein L, R ₁As above define with T, G is O, and T ₁Be O or NH; With

The ii) amine of formula XVIX

In the presence of coupling agent with the reaction of formula X compound, with preparation formula XVII compound.

Prove as this paper, the applicant finds to carry out the androgen receptor modulator compounds purification step in the presence of a kind of atoxic organic solvent and water such as second alcohol and water, for example carry out recrystallization from ethanol and water mixture, high productivity obtains a kind of high purity product with good crystallization-stable.In addition, using atoxic organic solvent/water to carry out purifying is because of its safety and cheap, and has avoided owing to use toxic organic solvent such as the caused biological hazard of hexane.In one embodiment, non-toxic organic solvent is an ethanol.

Therefore, in one embodiment, the invention provides the synthetic method of preparation androgen receptor modulator compounds described here, it mixture that comprises non-toxic organic solvent of use and water carries out androgen receptor modifier product crystalline purification step.In one embodiment, non-toxic organic solvent is an ethanol.In a specific embodiment, crystallisation step comprises and mixes ethanolic soln and the water that contains androgen receptor modifier, so that the androgen receptor modulator compounds crystallization.In further embodiment, present method further comprises the step of collecting androgen receptor modulator compounds by filtering.

Method of the present invention is suitable for scale operation, because all steps produce high-purity compound, so avoid finally reducing the complicated purification program of productive rate.Thereby the invention provides the synthetic method of the agonist compound of on-steroidal, it is large-scale synthetic that it can be used for industry, and high yield, highly purified product are provided simultaneously.Therefore in addition, described method of the present invention has used safety, environmental sound and cheap reagent and purification step, has avoided because use is toxic, any unwelcome toxicologic result abominable or that biologically astable reagent causes on the environment.

Technician under this area be it is evident that any non-toxic organic solvent is fit in the method for the invention, for example pure, as methyl alcohol or ethanol, aromatic substance such as toluene and dimethylbenzene, DMSO, THF, hexanaphthene or the like.

In one embodiment, non-toxic organic solvent is an ethanol.The ethanol of any grade and purity level is suitable.In one embodiment, ethanol is straight alcohol.In another embodiment, ethanol is the ethanolic soln that contains denaturing agent such as toluene, methyl alcohol etc.

Those skilled in the art understand, and work as T ₁When being O or NH, T is O or NH in the compound VIII ₂Therefore, T is OR in Compound I, and this reaction comprises that reaction makes OH be converted to the further step of OR as alkylogen R-X by using.T is NHCOR, NHCOCH in Compound I ₃The time, this reaction comprises by using as corresponding acyl chlorides ClCOR or ClCOCH ₃Reaction makes NH ₂Be converted to NHCOR or NHCOCH ₃Further step.

In one embodiment, coupling step defined above carries out in the presence of alkali.Any can XH part dehydrogenation is protonated (the phenol part when for example, X is O) also can use by coupling ground alkali.The non-limiting example of alkali is carbonate such as alkaline carbonate, for example yellow soda ash (Na ₂CO ₃), such as alkali metal hydrocarbonate such as sodium bicarbonate (NaHCO ₃), saleratus (KHCO ₃), alkalimetal hydride for example sodium hydride (NaH), potassium hydride KH (KH) and lithium hydride (LiH) or the like.

At leavings group L defined herein is the removable any group of chemical reaction known to common those skilled in the art.Suitable leavings group is halogen such as F, Cl, Br and I; Alkyl sulfonic ester (OSO ₂R), wherein R is an alkyl, for example metilsulfate (mesylate), trifluoromethyl sulfonic acid, ethyl sulfonate, 2,2,2-trifluoroethyl sulfonate, perfluoro butyl sulfosalt, aromatic yl sulphonate (OSO ₂Ar), wherein Ar is an aryl, for example p-toluenesulfonate (tosylate), benzene sulfonate, and it is replaced or does not replace by methyl, chlorine, bromine, nitro etc.; NO ₃, NO ₂, or vitriol, sulphite, phosphoric acid salt, phosphite, carboxylicesters, imido-ester, N ₂Or carbaminate.

Originally be reflected at suitable inert solvent or thinner such as tetrahydrofuran (THF), diethyl ether, aromatic amine such as pyridine; Aliphatics and aromatic hydrocarbons such as benzene, toluene and dimethylbenzene; Carry out smoothly in methyl-sulphoxide (DMSO), dimethyl formamide (DW) and the N,N-DIMETHYLACETAMIDE (DMAC).Originally be reflected at suitable carrying out in the temperature range, for example-20-120 ℃, for example near envrionment temperature.

Coupling reagent defined above is the reagent that carboxylic acid/thiocarboxylic acid of formula X can be become its response derivative, therefore can make separately amine and amine coupling generate acid amides/thioamides key.The response derivative of suitable carboxylic acid/thiocarboxylic acid is, acyl halide/sulfonyl halide for example is for example by acid/thioic acid sulfoacid and mineral acid muriate acyl group/sulphonyl chlorides of generating of thionyl chloride reaction for example; Mixed anhydride is for example by acid anhydride sour and chloro-formic ester such as isobutyl chloroformate reaction generation; Ester/the thioesters of opticity, for example ester/thioesters that generates as methyl alcohol, ethanol, Virahol, butanols or the reaction of N-hydroxybenzotriazole by acid/thioic acid sulfoacid and phenol, ester/thioesters or alcohol; Acyl group/sulfonyl trinitride, for example trinitride that generates by acid/thioic acid sulfoacid and trinitride such as the reaction of diphenylphosphoric acid trinitride; Acyl cyanide/sulfonyl prussiate is for example by acid and the prussiate prussiate that reaction generates as two second class phosphoric acid prussiates; Or the product of acid/thioic acid sulfoacid and carbodiimide such as dicyclohexylcarbodiimide reaction generation.

This reaction is in above describing suitable inert solvent or thinner, suitable is in the presence of alkali such as triethylamine, and as above-mentioned temperature range in carry out.

The biological activity of selective androgen conditioning agent compound

Androgen receptor modulator compounds that this paper provides is SARM (SARM) compound, and it has the androgen antagonist activity of on-steroidal part beyond expectation to androgen receptor.In addition, the part androgen receptor modulator compounds is irreversibly in conjunction with androgen receptor.And part androgen receptor modulator compounds of the present invention is an alkylating agent.

As this paper was desired, the androgen receptor modulator compounds that the present invention suitably replaces had following purposes: a) male contraceptive; B) the various symptoms relevant of treatment with hormone, for example with old age male male sex hormone reduce relevant disease (ADAM), for example fatigue, dysthymia disorders, sexual desire reduction, sexual dysfunction, erective dysfunction, hypogonadism, osteoporosis, trichomadesis, anaemia, obesity, muscle wasting, osteopenia, osteoporosis, benign prostatic hyperplasia, in the change and the prostate cancer of mood, insight; C) to the treatment of female male sex hormone decline (ADIF) diseases related, for example sexual dysfunction, sexual desire minimizing, hypogonadism, muscle wasting, osteopenia, osteoporosis are to the change of insight and mood, depression, anaemia, alopecia, obesity, endometriosis, mammary cancer, uterus carcinoma and ovarian cancer; D) treating and/or preventing acute and/or chronic muscle wasting disease; E) prevent and/or treat dry eyes illness f) the oral androgenic replacement therapy; G) reduce prostate cancer sickness rate, interrupt or impel the deterioration of prostate cancer; And/or h) cancer cell specific induction of apoptosis.

As used herein, the acceptor of extracellular signaling molecule is referred to as " cell signal acceptor " (cell signaling receptor).Many cell signal acceptors are transmembrane proteins of cell surface; When they during in conjunction with extracellular signaling molecule (being part), thereby they become the activation form and cause the intracellular signal cascade that changes cell behavior.On the contrary, acceptor is in cell sometimes, and the signal part must enter cell and activate them; Thereby these signaling molecules must be enough little and hydrophobic, to cross over the cytoplasmic membrane diffusion.

Steroid hormone be directly cross over target cell plasma membrane diffusion or transhipment and with an example of the little hydrophobic molecule of born of the same parents' inner cell frizzled receptor bonded.The structurally relevant and formation intracellular receptor superfamily (or steroid hormone receptor superfamily) of these acceptors.Steroid hormone receptor comprises PgR, estrogen receptor, androgen receptor, glucocorticoid receptor and mineralcorticoid receptor.What the present invention is directed in one embodiment, is androgen receptor.

Except that part was incorporated into acceptor, acceptor can be blocked to prevent the part combination.When material and receptors bind, the three-dimensional structure of this material is fit to the space of the three-dimensional structure formation of acceptor in the ball bag configuration (ball and socketconfiguration).The suitable more bag of ball, then it is closely held more.This phenomenon is called affinity.If a kind of affinity of material is greater than original hormone, it will and combine binding site more continually with the hormone competition so.In case combination, signal can pass to cell by acceptor, makes cell make response in some way.This is called activation.By activating, activated receptors is directly controlled transcribing of some specific gene then.But for activating cells, material and acceptor may have some attribute outside the affinity.Between material atom and acceptor atom, can form chemical bond.Sometimes, this causes the change of acceptor configuration, thereby is enough to start activation process (being called signal transduction).

In another embodiment, the present invention is directed to the SARM compound, they are agonist compounds.Receptor stimulant is bind receptor and the material that activates them.Receptor antagonist is bind receptor and their material of passivation.Therefore in one embodiment, androgen receptor modulator compounds of the present invention is used for combination and passivation steroid hormone receptor.In one embodiment, agonist compounds of the present invention is a kind of antagonist that is used in conjunction with androgen receptor.At other in one embodiment, compound has the high affinity with androgen receptor.

Analysis is to determine that whether androgen receptor (AR) agonist or antagonist are known to compound of the present invention for those skilled in the art.For example, keep and/or promote to comprise the ability (as measuring weight) of tissue such as the prostate gland of androgen receptor and seminal vesicle growth, can determine the agonist activity of androgen receptor by the monitoring androgen receptor modulator compounds.Suppress to contain the ability of the tissue growth of androgen receptor by the monitoring androgen receptor modulator compounds, can measure the antagonistic activity of androgen receptor.

Androgen receptor is the androgen receptor of any species, for example Mammals.In one embodiment, androgen receptor is human androgen receptor.

Compound of the present invention can be reversible or irreversibly in conjunction with androgen receptor.In one embodiment, androgen receptor modulator compounds is reversibly in conjunction with androgen receptor.In another embodiment, androgen receptor modulator compounds is reversibly in conjunction with the human androgen receptor.Reversibly bind receptor means that compound can separate from acceptor in conjunction with the back.

In another embodiment, androgen receptor modulator compounds is irreversibly in conjunction with androgen receptor.In one embodiment, androgen receptor modulator compounds is irreversibly in conjunction with mammiferous androgen receptor.In another embodiment, androgen receptor modulator compounds is irreversibly in conjunction with the human androgen receptor.Therefore, in one embodiment, compound of the present invention may comprise a kind of alkylating functional group of androgen receptor (for example formation of covalent linkage) (for example avidity mark) that makes.Therefore in this case, this compound is an alkylating agent, and it is bind receptor irreversibly, and therefore can not be by steroid such as endogenic ligand DHT and testosterone replacement." alkylating agent " defined herein is the reagent that utilizes cellular component such as DNA, RNA or enzyme alkanisation (generation covalent linkage).It is a kind of chemical preparations of high reaction activity, alkyl can be introduced bioactive molecules and stop their peculiar function thus.Alkylation partly is the electrophilic group that influences the nucleophilic part in cell in the component.For example, in one embodiment, alkylation group is an isocyanate moiety, its be with cellular component in nucleophilic group (N, O, S etc.) generate the electrophilic group of covalent linkage.In another embodiment, alkylation group is the isothiocyanic acid ester moiety, is the electrophilic group that nucleophilic group (N, O, S etc.) in another and the cellular component forms covalent linkage.In another embodiment, alkylation group is haloalkyl (CH ₂X wherein X is a halogen), be with cellular component in nucleophilic group generate the electrophilic group of covalent linkage.In another embodiment, alkylation group is haloalkyl-amino (NHCOCH ₂X, wherein X is a halogen), in cellular component, generate the electrophilic group of covalent linkage with nucleophilic group.

In one embodiment, androgen receptor modulator compounds of the present invention is the androgen receptor agonist of the irreversible fixation Mammals such as the mankind's androgen receptor.In one embodiment, this compound is an alkanisation reagent.

In one embodiment, the present invention further provides a kind of with the method for SARM compound in conjunction with androgen receptor, it comprises SARM compound of the present invention and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, the perhaps step that contacts with androgen receptor of their arbitrary combination, wherein the SARM compound adds with the effective amount in conjunction with androgen receptor.

In another embodiment, the present invention further provides a kind of with the SARM compound irreversibly in conjunction with the method for androgen receptor, it comprises SARM compound of the present invention and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, the perhaps step that contacts with androgen receptor of their arbitrary combination, wherein the SARM compound adds with the amount in conjunction with androgen receptor effectively irreversibly.

In another embodiment, the present invention further provides the alkylating method of a kind of androgen receptor, it may further comprise the steps: with SARM compound of the present invention and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination contacts with androgen receptor with the amount of effective alkylation androgen receptor.

In another embodiment, the invention provides a kind of spermatogenetic method that in patient's body, suppresses, it may further comprise the steps: the amount that produces with effective inhibition sperm is with SARM compound of the present invention and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, and perhaps their arbitrary combination contacts with patient's androgen receptor.

In another embodiment, the invention provides a kind of in the male patient body method of contraception, it may further comprise the steps: the amount that produces with effective inhibition sperm is with SARM compound of the present invention and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination is used to the patient, causes effective contraception thus in patient's body.

In another embodiment, the present invention further provides a kind of method of hormonotherapy, it may further comprise the steps: with effectively in conjunction with the amount of androgen receptor with SARM compound of the present invention and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination contacts with androgen receptor, to reach the effect that effective change male sex hormone relies on illness.

In another embodiment, the invention provides a kind of method of hormone replacement therapy, it may further comprise the steps: to reach amount that effective change male sex hormone relies on illness with SARM compound of the present invention and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination contacts with patient's androgen receptor.

In another embodiment, the present invention further provides the method that a kind of treatment has hormone associated conditions patient, it may further comprise the steps: so that SARM in conjunction with the amount of androgen receptor with SARM compound of the present invention and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination contacts with androgen receptor, changes the effect that male sex hormone relies on illness to reach.

Male sex hormone dependence illness according to the present invention's treatment can comprise and aging diseases associated, as hypogonadism, muscle wasting, red corpuscle the other diseases that (erythropoiesis), osteoporosis and other any later stage depend on low male sex hormone (for example testosterone) level takes place.

In another embodiment, the present invention further provides a kind of method for the treatment of the carcinoma of prostate patient, it may further comprise the steps: so that effectively the amount of treatment carcinoma of prostate is with SARM compound of the present invention and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound in the patient, perhaps their arbitrary combination is used the patient.

In another embodiment, the invention provides a kind of method of in the patient, preventing carcinoma of prostate, it may further comprise the steps: so that effectively the amount of prevention carcinoma of prostate is with SARM compound of the present invention and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound in the patient, perhaps their arbitrary combination is used the patient.

In another embodiment, the present invention further provides a kind of method that delays the development of carcinoma of prostate patient's prostate cancer disease, it may further comprise the steps: with SARM compound of the present invention and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination is used the patient with the amount that effectively delays patient's prostate cancer disease development.

In another embodiment, the present invention further provides a kind of method of preventing the recurrence of patient's prostate cancer disease, it may further comprise the steps: with SARM compound of the present invention and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination is used the patient with the amount of effective prevention patient's prostate cancer disease recurrence.

In another embodiment, the present invention further provides a kind of method for the treatment of the recurrence of patient's prostate cancer disease, it may further comprise the steps: with SARM compound of the present invention and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination is used the patient with the amount of effective treatment patient's prostate cancer disease recurrence.

In addition, because the stimulation of androgen receptor promotes the generation of tears, therefore androgen receptor modulator compounds of the present invention may be used for treating in ocular disorders.So, according to another embodiment, the invention provides a kind of method for the treatment of dry eye patients dry eyes illness, it may further comprise the steps: with SARM compound of the present invention and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination is used described patient with effective amount for the treatment of patient's dry eyes illness.

A kind of method of the patient's of prevention dry eyes illness is provided according to another embodiment of the invention, it may further comprise the steps: with SARM compound of the present invention and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination is used described patient with effective amount of preventing patient's dry eyes illness.

In another embodiment, the invention provides a kind of method of inducing the prostate cancer cell apoptosis, it may further comprise the steps: with the amount of effective cancer cell specific induction of apoptosis with SARM compound of the present invention and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination and cells contacting.

As defined herein, " apoptosis " or apoptosis are a kind of forms of necrocytosis, and wherein the incident of programmatic order causes cell to be eliminated and the not regional towards periphery objectionable impurities that discharges.Apoptosis is by removing senile cell, unnecessary cell and unsound cell, in development with keep in the health and play an important role.

As defined herein, " contact " refers to androgen receptor modulator compounds of the present invention is introduced in the sample in test tube, flask, tissue culture, chip (chip), array (array), flat board, microplate, the kapillary etc., and hatches being enough to make under enzyme and the androgen receptor modifier bonded temperature and time.Sample is conventionally known to one of skill in the art with method conjugated protein or that other specific binding component contacts, and can be selected according to the type of the experimental program of taking.The incubation method also is a standard, and is conventionally known to one of skill in the art.

In another embodiment, term " contact " refers to androgen receptor modulator compounds of the present invention is introduced in patients receiving treatment's the body, and allows androgen receptor modulator compounds to contact with androgen receptor in vivo.

As used herein, term " treatment " comprises preventative and avoids (remitative) disorderly treatment.As used herein, term " minimizing ", " compacting " and " inhibition " have dwindling of their common senses or reduce the meaning.As used herein, term " progress " (progression) refer to extend range or serious, progress (advancing), grow or become worse.As used herein, term " recurrence " refers to palindromia after the remission.As used herein, term " delay " refers to prevention, stops, slows down, delays, stops or hinders.

As used herein, term administering " relate to androgen receptor modulator compounds of the present invention and contact with the patient.As used herein, can externally use, for example in test tube, or use in the body, for example in the living organism such as the mankind's cell or biological tissue.In one embodiment, the present invention includes with compound of the present invention the patient is used.

The requirement of referring to property of as used herein term " sexual desire ".

Term as used herein " erection " refers to erectile ability.Erectile tissue be a kind of can be by the expansion expansion of many blood vessels that it comprised and the tissue of hardening.

" hypogonadism " is a kind of because the unusual illness that reduces of the sexual gland functional activity of following growth and sexual development to delay." osteopenia " refers to the reduction of bone calcification or density.This term comprises whole Skeletal systems of mentioning this situation.

" osteoporosis " refers to because the osteopenic bone of following that calcium and bone protein consumption cause attenuates.Osteoporosis causes the people to fracture easily, and its treatment often slowly also is difficult to cure.Unsighted osteoporosis can cause posture change, physical abnormality and handiness to reduce.

" BPH (benign prostatic hyperplasia) " is meant prostatic nonmalignant increase, is the abnormality proliferation of the most common non-malice of finding at any internal organs, and is the major reason of bull morbidity.Surpass 75% the man more than 50 years old and suffer from BPH, to more than 90 year old sickness rate reach 88%.BPH often causes passing the extruding gradually of prostate gland (prostate gland section urethra) urethra part.Because incomplete emptying of bladder and urgent urination, the patient of this cause of disease stands the frequent urine of thinking.The obstruction that urine flows can cause generally lacking the control to urinating, and comprises the difficulty when wanting to begin to urinate, and as difficult because of not urinating and flow at prevention urine from the bladder emptying, this disease is called the excessive urinary incontinence, can cause urinary tract obstruction and urinate failure.

" insight " refers to the process of understanding, the process of particularly realizing the truth, be familiar with, consider, learn and judge.Insight and psychology, linguistics, computer science, neuroscience, mathematics, individual ecology are relevant with the philosophy field.Term " mood " refers to the mood or the state of thought.Expect as this paper, change any change in insight and/or mood that refers to positive or negative.

Term " dysthymia disorders " refers to the disease that comprises health, mood and thought, and it influences a people's diet, mode and people of sleep feels modes own and the thinking affairs.The sign of dysthymia disorders and symptom comprise activity are lost interest, lose the appetite or eats and drinks immoderately, do not have emotion expression service, shortage mood, despair, pessimism, crime sense or helpless, avoid social, tired, sleep disordered, worried pile up, remember (decline) or (losing) resolution, uneasiness, irritability, headache, digestive disorders or chronic pain.

Term " trichomadesis " medically is referred to as alopecia, refers to the alopecia of the very common male alopecia type of picture.Typical alopecia starts from trichomadesis scrappy on scalp, develops into alopecia completely sometimes, and or even the coming off of body hair.Trichomadesis influences male and female simultaneously.

" anaemia " refers to be had in blood less than the red blood corpuscle of normal number or less than the hemochrome of normal quantity.Therefore, blood descends to the transportcapacity of oxygen.The patient who suffers from anaemia may feel tired easily and tired, seeming does not have color, causes palpitaition and breathe usually.The reason that causes anaemia has four fundamental factor: a) lose blood (bleeding); B) haemolysis (erythrocytic excessive destruction); C) red blood corpuscle is underproduce; D) there are not enough Hb A hemoglobin adults.Many form of anemia are arranged here, comprise aplastic anemia, benzolism, Fanconi anaemia, neonatal hemolytic, hereditary spherocytosis, hypoferric anemia, osteopetrosis, pernicious anemia, drepanocytosis, thalassemia, myelodysplastic syndrome and various bone marrow disease.Expect that as this paper androgen receptor modulator compounds of the present invention is preventing and/or treating any one or a plurality of form of anemia listed above is useful.

" obesity " refers to the state that exceeds people's normal weight.If people exceeds 20% of his ideal body weight and just is considered to fat traditionally.NIH (NIH) more properly obesity is defined as body weight exceed weight indicator (BMI) 30 or more than.Obesity often is multifactorial, and it is based on heredity and behavial factor.What obesity caused is a kind of important factor of health problem.It has increased and develops into numerous disease and comprise: 2 types (beginning of growing up) diabetes; High blood pressure (hypertension); Apoplexy (cerebrovascular accident or CVA); Heart attack (myocardial infarction or MI); (congestive heart failure) in heart failure; Cancer (definite type such as prostate cancer and colorectal carcinoma and the rectum cancer); Gallbladdergallstonecholetithiasis and gallbladder disease (cholecystitis); Gout and urarthritis; Knee, hip and waist osteoarthritis (degenerative arthritis); Sleep apnea (can't between sleep period, normally breathe low blood oxygen); And pickwickian syndrome (obesity, blush, oxygen supply deficiency (underventilation) and drowsiness).Expect that as this paper term " obesity " comprises any one the above and fat relevant illness and disease.Therefore, androgen receptor modulator compounds of the present invention can be used for preventing and/or treating obesity and any one the above illness and disease relevant with obesity.

Prostate cancer is U.S. man one of the most recurrent cancer, and the new diagnosed SARS case of hundreds of thousands of is arranged every year.Unfortunately, surpassing 60% new diagnosed SARS case is can't treat and pathology late period that prognosis is not good.A kind of method that addresses this problem is also to reduce advanced prostate cancer patient's number thus by screening procedure (screening programs) discovery prostate cancer early.Yet another strategy is the medicine of development prevention prostate cancer.1/3rd surpass 50 years old man has latent prostate cancer form, and it may activate and become life-threatening clinical prostate cancer form.Shown that latent tumor of prostate occurrence frequency was all increasing every 10 years from 50 years old (5.3-14%) to 90 years old (40-80%) substantially.Between literate, nationality and the race number of latent prostate cancer be identical, yet it is significantly different to have aggressive oncogenesis frequency clinically.So just can suppose that environmental factors may play effect when activating the latent prostate cancer.

In one embodiment, method of the present invention comprises androgen receptor modulator compounds using as unique activeconstituents.Yet; protection scope of the present invention comprises hormonotherapy, prostate cancer therapy, delays the prostate cancer progress and prevents and/or treats the method that prostate cancer recurs that it comprises androgen receptor modulator compounds using in conjunction with one or more medicine products.Material, selective estrogen receptor modulators (SERM), Progesterone, oestrogenic hormon, PDE5 inhibitor, apomorphine, diphosphonate and one or more auxiliary androgen receptor modifiers (SARM) that medicament production works including, but not limited to: LHRH analogue, reversible androgen antagonist, antiestrogen, anticarcinogen, 5-alpha reductase inhibitor, arimedex, progesterone, by other nuclear hormone receptors.

Therefore, in one embodiment, method of the present invention comprises that SARM compound and LHRH analogue bonded use.In another embodiment, method of the present invention comprises that SARM compound and reversible androgen antagonist bonded use.In another embodiment, method of the present invention comprises that SARM compound and antiestrogen bonded use.In another embodiment, method of the present invention comprises that SARM compound and cancer therapy drug bonded use.In another embodiment, method of the present invention comprises that SARM compound and 5-alpha reductase inhibitor bonded use.In another embodiment, method of the present invention comprises that SARM compound and arimedex bonded use.In another embodiment, method of the present invention comprises that SARM compound and progesterone bonded use.In another embodiment, method of the present invention comprises the SARM compound and uses by the material bonded that other nuclear hormone receptors work.In another embodiment, method of the present invention comprises that SARM compound and reversible androgen antagonist bonded use.In another embodiment, method of the present invention comprises that SARM compound and selective estrogen receptor modulators (SERM) bonded use.In another embodiment, method of the present invention comprises that SARM compound and Progesterone bonded use.In another embodiment, method of the present invention comprises that SARM compound and oestrogenic hormon bonded use.In another embodiment, method of the present invention comprises that SARM compound and PDE5 inhibitor bonded use.In another embodiment, method of the present invention comprises that SARM compound and apomorphine bonded use.In another embodiment, method of the present invention comprises that SARM compound and diphosphonate bonded use.In another embodiment, method of the present invention comprises that other androgen receptor modifier (SARM) bonded of SARM compound and one or more uses.

In one embodiment, the invention provides a kind of SARM compound of the present invention and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their bonded composition of comprising.

In another embodiment, the invention provides a kind of medicinal compositions and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound that comprises SARM compound of the present invention, the pharmaceutical composition of perhaps their combination, and appropriate carriers or thinner.

As used herein, " pharmaceutical composition " refers to treat the androgen receptor modifier of significant quantity with suitable thinner, sanitas, solubilizing agent, emulsifying agent, adjuvant and/or carrier.As used herein, " treatment significant quantity " refers to provide the amount of curative effect for given illness and application program.This composition is liquid or freeze dried or other exsiccant prescriptions, and comprise various buffer compositions (Tris-HCl for example, acetate, phosphoric acid salt), the thinner of pH and ionic strength, prevent to be adsorbed in additive such as the albumin or the gelatin on surface, stain remover (polysorbas20 for example, tween 80, Pluronic F68, bile salt), solubilizing agent (glycerine for example, polyoxyethylene glycol), antioxidant (xitix for example, Sodium Pyrosulfite), sanitas (thimerosal for example, phenylcarbinol, p-Hydroxybenzoate), increment (bulking) material or tension force properties-correcting agent (lactose for example, N.F,USP MANNITOL), polymkeric substance covalently bound as be connected in proteic polyoxyethylene glycol, cooperate with metal ion, or material mixed polymkeric substance such as poly(lactic acid), polyglycolic acid, in the particle product of hydrogel etc. or on it, perhaps mix liposome, micro emulsion, micella, the single or multiple lift vesica, on blood shadow or the spheroplast.This composition will influence rate of release and the interior clearance rate of body in physical condition, solubleness, stability, the body.Controlled release or slow releasing composition are included in the prescription in the lipotropy storage storehouse (depot) (for example lipid acid, wax, oil).

The present invention also comprises with polymkeric substance (for example poloxamer or poloxamines) coated granules composition.Other embodiment of composition of the present invention comprises and is used for various route of administration, comprises parenteral, through lung, intranasal and oral particle form, protectiveness dressing, proteinase inhibitor or penetration enhancers.In one embodiment, pharmaceutical composition is used through following approach: parenteral, cancer knurl other (paracancerally), through mucous membrane, in skin, intramuscular, intravenously, intracutaneous, subcutaneous, intraperitoneal, intravaginal, ventricle, in encephalic and the tumour.In addition, as used herein, " pharmaceutically acceptable carrier " is well known to those skilled in the art, and includes but not limited to 0.01-0.1M and preferred 0.05M phosphate buffered saline buffer or 0.8% salt solution.In addition, this type of pharmaceutically acceptable carrier can be moisture or non-aqueous solution, suspension and emulsion.Examples of non-aqueous is propylene glycol, polyoxyethylene glycol, vegetables oil such as sweet oil, and injectable organic ester such as ethyl oleate.Aqueous carrier comprises water, ethanol/water solution, comprises the emulsion or the suspension of salt solution and buffering medium.

The parenteral carrier comprises sodium chloride solution, Ringer ' s dextrose, dextrose and sodium-chlor, lactic acid Ringer ' s or fixed oil.Intravenous vehicles comprises liquid and nutritional supplement, dielectric medium fill-in as based on those of Ringer ' s dextrose, or the like.Also can contain sanitas and other additive, for example biocide, antioxidant, finishing composition (collatingagents), rare gas element etc.

Controlled release or slow releasing composition are included in the prescription in the lipotropy storage storehouse (for example lipid acid, wax, oil).The present invention also comprises with polymkeric substance (for example poloxamer or poloxamines) coated granules composition, and compound is coupled on antibody, part or the antigen at the tissue specificity acceptor, perhaps is coupled on the part of tissue specificity acceptor.

Other embodiment of composition of the present invention comprises and is used for various route of administration, comprises parenteral, through lung, intranasal and oral particle formulation, protectiveness dressing, proteinase inhibitor or penetration enhancers.

The compound of the covalently bound modification of known multipolymer, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone or polyproline by water-soluble polymers such as polyoxyethylene glycol, polyoxyethylene glycol and polypropylene glycol is after intravenous injection, in blood, demonstrate than remarkable longer transformation period (Abuchowski etc., 1981 of the compound of corresponding unmodified; Newmark etc., 1982; With Katre etc., 1987).These modifications also may increase solubleness, the elimination of compound in the aqueous solution assembles, improves the physics and the chemical stability of compound, and greatly reduces the immunogenicity and the reactivity of compound.As a result, by giving this polymkeric substance-compound adducts (abducts), can realize the biological activity of expecting to compare lower frequency and lower dosage with the compound of unmodified.

In another embodiment, pharmaceutical composition can be used through controlled release system.For example, can use venoclysis, implantable osmotic pump, transdermal patch, liposome or other method of application to give medicine.In one embodiment, can use pump (referring to Langer, supra; Sefton, CRC Crit.Ref.Biomed.Eng.14:201 (1987); Buchwald etc., Surgery 88:507 (1980); Saudek etc., N.Engl.J.Med.321:574 (1989).In another embodiment, can use polymeric material.In another embodiment, controlled release system can be positioned over treatment target such as brain near, thereby a part that only needs body dose is (referring to for example Goodson, in Medical Applications OfControlled Release, supra, vol.2, pp.115-138 (1984).Other controlled release system (Science 249:1527-1533 (1990)) has been discussed in the summary of Langer.

Pharmaceutical preparation can only comprise SARM, perhaps also comprise pharmaceutically acceptable carrier, and can be solid or liquid form, as tablet, powder, capsule, pill, solution, suspensoid, elixir, emulsion, gelifying agent, emulsifiable paste or suppository, comprise rectum and urethral suppositories.Pharmaceutically acceptable carrier comprises gel, starch, sugar, cellulosic material and their mixture.The pharmaceutical preparation that contains SARM can be given and the experimenter by for example subcutaneous implantation piller: in another embodiment, piller provides the sustained release of SARM in one period.Preparation also can pass through intravenously, intra-arterial or intramuscularly liquid preparation, orally give liquid or solid preparation, or gives by topical application.Also can use by using rectal suppository or urethral suppositories to finish.

Pharmaceutical preparation of the present invention can prepare by known dissolving, mixing, granulation or tabletting method.For Orally administered, derivative that can tolerate SARM or its physiology such as salt, ester, N-oxide compound etc. mix with additive such as carrier, stablizer or inert diluent that routine is used for this purpose, and be converted into the suitable form that is used to use by ordinary method, as tablet, coated tablet, hard or soft gelatin capsule, water, alcohol or oil solution.The example of suitable inert support is conventional tablet matrix such as lactose, sucrose or W-Gum and tackiness agent such as Sudan Gum-arabic, W-Gum, gelatin, perhaps with disintegrating agent such as W-Gum, yam starch, alginic acid, perhaps with lubricant such as stearic acid or Magnesium Stearate.

The suitable oily carrier or the example of solvent are vegetables oil or animal oil, as sunflower oil or Oils,glyceridic,cod-liver.Preparation can be used as dried particle or wet granular obtains.For parenteral is used (subcutaneous, intravenously, intra-arterial or intramuscularly), the derivative of androgen receptor modifier agent or on-steroidal agonist or the tolerance of their physiology such as salt, ester, N-oxide compound etc. are changed into solution, suspension or emulsion, if expectation, for example solubilizing agent or other adjuvant are prepared with the habitual and material that is suitable for this purpose.Example is: sterile liquid Ru Shui and oil, add or do not add tensio-active agent and the acceptable adjuvant of other pharmacy.The example of oil is to derive from oil, animal, plant or synthetic oil, for example peanut oil, soybean oil or mineral oil.Usually, water, salt solution, the dextrose aqueous solution and relevant sugar soln, and glycol such as propylene glycol or polyoxyethylene glycol be preferred liquid vehicle, particularly uses for injection solution.

The preparation of drug combination that contains active ingredient is well known in the art.Usually, these preparation of compositions are become to be administered to the polypeptide aerosol of pharynx nasalis, perhaps be prepared into injecting fluid solution or suspension, yet, also can be prepared into the solid form that is dissolved in or is suspended in before being adapted at injecting in the liquid.Preparation also can be emulsified.The active treatment composition is acceptable and compatible with the activeconstituents mixed with excipients with pharmacy usually.Suitable vehicle is for example water, salt solution, dextrose, glycerine, ethanol etc. and their combination.

In addition, if expectation, composition can contain minor amounts of auxiliary substances, and as wetting agent or emulsifying agent, pH buffer reagent, these auxiliary substances improve the validity of activeconstituentss.

Active ingredient can be filled a prescription in composition with neutral pharmacologically acceptable salts form.Pharmacologically acceptable salts comprises and adds sour salify (forming with the free amine group of polypeptide or antibody molecule), and they are the salt that forms with mineral acid example hydrochloric acid or phosphoric acid, or the salt that forms with organic acid such as acetic acid, oxalic acid, tartrate, mandelic acid, or the like.The salt that is formed by free carboxyl group also can derive from mineral alkali such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide or ironic hydroxide etc., derives from organic bases such as Isopropylamine, Trimethylamine 99,2-ethylamino-ethanol, Histidine, PROCAINE HCL, PHARMA GRADE etc.

For to the body surface topical application, for example use emulsifiable paste, gelifying agent, drops etc., the derivative of preparation androgen receptor modifier or non-steroidal agonist compounds or the tolerance of their physiology such as salt, ester, N-oxide compound etc., and with in the physiology acceptable diluent, the solution, suspension or the emulsion form that are with or without pharmaceutical carrier are used.

In another embodiment, active compound can be at vesica, especially transport in the liposome (referring to Langer, Science 249:1527-1533 (1990): Treat etc., inLiposomesin the Therapy of infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp.353-365 (1989); Lopez-Berestein, ibid, pp.317-327; Generally referring to, ibid).

For medical use, the salt of androgen receptor modifier or non-steroidal agonist compounds is pharmacologically acceptable salts.Yet other salt comes in handy in each compound of the present invention of system or their pharmacologically acceptable salts.The suitable pharmacologically acceptable salts of compound of the present invention comprises and adds sour salify, it can, for example mix with the solution of the acceptable acid of pharmacy and make the acceptable sour example hydrochloric acid of described pharmacy, sulfuric acid, methylsulfonic acid, fumaric acid, toxilic acid, succsinic acid, acetic acid, phenylformic acid, oxalic acid, citric acid, tartrate, carbonic acid or phosphoric acid by the solution that makes compound of the present invention.

Following examples are used for more fully setting forth the preferred embodiments of the invention, yet not as restriction wide protection domain of the present invention.

The experimental detail part

Experimental technique

Clone

The source of the clone that is used to study described herein is as shown in the following Table 1:

Table 1

Clone	Morphology	Expression of receptor	The source	Case
Clone	Morphology	Expression of receptor	The source	Case	LNCaP	Epithelium	Male sex hormone; Oestrogenic hormon	Left front clavicle lymphoglandula pin suction examination of living tissue	Suffered from the male sex white man of D1 stage prostate cancer in 50 years old
DU145	Epithelium		Transitivity CNS damage	The 69 years old male sex white man who suffers from metastatic prostate cancer and 3 years lymphoid leukemias	LNCaP	Epithelium	Male sex hormone; Oestrogenic hormon
DU145	Epithelium		Transitivity CNS damage		PC-3	Epithelium		Prostate gland transitivity marrow	The 62 years old Caucasia male sex who suffers from IV degree adenocarcinoma of prostate
PPC-1 (former generation prostate cancer-1)	Epithelium		The prostate-urethra excision	Suffer from the D2 stage and do not break up 67 years old male sex Black people of prostate cancer	PC-3	Epithelium		Prostate gland transitivity marrow

TSU	Epithelium	The uterine neck metastatic carcinoma	The 73 years old Japanese male sex who suffers from the adenocarcinoma of prostate of medium differentiation
TSU	Epithelium	The uterine neck metastatic carcinoma					Tubercle
TCCSUP	Epithelium	The Analpastic metastatic cell cancer of bladder neck	67 years old elderly woman suffering from IV degree bladder cancer				Tubercle
TCCSUP	Epithelium	The Analpastic metastatic cell cancer of bladder neck		HT-29	Epithelium	The urine hormone acceptor, vitamins D	Colorectum gland cancer	44 years old Caucasia women
CV-1	Inoblast	Normal kidney	The male adult monkey of cercopithecus aethiops (141 days)	HT-29	Epithelium	The urine hormone acceptor, vitamins D	Colorectum gland cancer	44 years old Caucasia women
CV-1	Inoblast	Normal kidney	The male adult monkey of cercopithecus aethiops (141 days)	MCF-7			Mammary cancer

The cell growth conditions

Cultivate PPC-1, LNCaP, TSU, PC-3 and DU145 to PRMI-1640 culture medium supplemented 10% foetal calf serum (FBS) that contains the 2mM L-glutaminate.Cell is at 5%CO ₂Cultivate in/95% atmospheric moisture and 37 ℃.

Sulphonyl rhodamine B (Sulforhodamine B, SRB) test

The SRB test is used for measuring cell quantity at cytotoxicity experiment.Use following scheme:

1. cell separates with 0.25% trypsinase.

2. the test culture is at 96-hole microwell plate (every hole 200uL growth medium; Every hole 1,000-200,000 cell) the middle cultivation.

3. with 50uL 50%TCA (4 ℃) fixed culture.(details is referring to cell fixation protocol).

4. in 1% acetate, dyeed 10 minutes with 50uL 0.4% (weight/volume) SRB.

5. remove the also rapid * of SRB and remove unconjugated dyestuff 5 times with 1% acetic acid solution rinsing.**

6. spend the night air-dry culture up to there not being moisture.

7. do not cushion Tris alkali with 200uL on the platform vibrator (10mM, pH10.5) SRB of dissolved cell protein bound is 30 minutes shaking.

8. read light absorption ratio at 540nm.

^*Carry out cleaning process fast to stop the desorption of protein bound SRB

^*Remove residual washing soln fully by the sheet glass on the rapid tip-tap rinse bath.

Fixing adherent in the cell of plastic-substrates

Following scheme is used for fixing cell:

A. with 50uL 50%TCA (4 ℃) gradually layer in each hole on the growth medium to prepare the TCA of 10% last concentration.

B. 4 ℃ of incubation cultures 1 hour.

C. with tap water washing culture 5 times to remove TCA, growth medium, lower molecular weight metabolite and serum protein.

D. air-dry flat board is up to there not being moisture.

The result

Embodiment 1

The cytotoxicity of compound in different clone

R-CTF-T-CA-1, R-CTF-T-BA-1, S-NTBA, compound V, 5 FU 5 fluorouracil and taxol in the prostate cancer cell line (DU145, PC-3, TSU, PPC-1 and LNCaP), the IC of other cancerous cell line (TCCSUP, HT-29) and control cells system (CV-1) ₅₀As show 2A and show 2B and shown in Figure 1.The result shows, compares with non-prostate cancer cell line with other prostate cancer cell lines of not expressing AR, and compound V has high selectivity for the LNCaP prostate cancer cell line of expressing AR.These results show that the potential conduct of compound V treats effective preparation of carcinoma of prostate separately.

Table 2A-prostate cancer cell line

Other tumor cell line and contrast of table 2B-

Embodiment 2

Compound is in the cytotoxicity of LNCaP clone

The IC of R-CTF-T-CA-1, R-CTF-T-BA-1, S-NTBA and the compound V of the LNCaP prostate cancer cell line of expressing at AR ₅₀Shown in table 3, Fig. 2 (LNCaP) and Fig. 3 (CV-1).Handle after 24 hours, R-CTF-T-CA-1, R-CTF-T-BA-1, S-NTBA and compound V are at the IC of LNCaP clone ₅₀Be respectively 11.2 μ M, 3.5 μ M, 4.4 μ M and 39.6 μ M.Handle after 6 days, R-CTF-T-CA-1, R-CTF-T-BA-1, S-NTBA and compound V are at the IC of LNCaP clone ₅₀Be respectively 8.1 μ M, 1.7 μ M, 2.1 μ M and 33.6 μ M.Compare with the result of the CV-1 clone that contrasts, handle 4 days R-CTF-T-CA-1, R-CTF-T-BA-1 and the IC of S-NTBA ₅₀Be respectively 13.9 μ M, 4.2 μ M and 4.9 μ M (compound V-NA).The result shows that system compares with control cells, and compound V has high selectivity to the LNCaP prostate cancer cell line that AR expresses.These results show that the potential conduct of compound V treats effective preparation of carcinoma of prostate separately.

The different treatment of table 3-R-CTFs in LNCaP and CV-1

Embodiment 3

The cytotoxicity of compound in PC-3 clone

IC at R-CTF-T-CA-1, R-CTF-T-BA-1, S-NTBA and the 5 FU 5 fluorouracil of PC-3 prostate gland metastatic bone myelocytic series ₅₀As table 4 and shown in Figure 4.Handle after 24 hours the IC of R-CTF-T-CA-1, R-CTF-T-BA-1, S-NTBA and 5 FU 5 fluorouracil ₅₀Be respectively 22.1 μ M, 5.8 μ M,＞50 μ M and 22-50 μ M.Handle after 4 days the IC of R-CTF-T-CA-1, R-CTF-T-BA-1, S-NTBA and 5 FU 5 fluorouracil ₅₀Be respectively 16.8 μ M, 4.3 μ M, 18.0 μ M and 10.9 μ M.

Under the table 4-different treatment in PC-3 the IC of R-CTF-Ts ₅₀Quantity

Embodiment 4

The expansion Study of cytotoxicity of compound in different clone

After 1 and 4 day, is the IC of (CV-1), DJ1-31, DJ1-29, S-NTBA and compound V in different prostate cancer cell line (DU145, PC-3, TSU, PPC-1 and LNCaP), other cancerous cell line (TCCSUP, HT-29 and MCF-7) and control cells with the medicine cultivation ₅₀As show shown in 5A and the 5B.The result shows, do not show that with other prostate cancer cell line of AR compares with non-prostate cancer cell line, and compound V has high selectivity for the LNCaP prostate cancer cell line of expressing AR.These results show that the potential conduct of compound V treats effective preparation of carcinoma of prostate separately.

Table 5A-prostate cancer cell line

Other cancerous cell line and contrast of table 5B-

Embodiment 5

Compound is to the apoptosis effect of different clones

Measure DJ1-31, DJ1-29, S-NTBA and compound V to different prostate cancer cell lines (DU145, PC-3, TSU, PPC-1 and LNCaP), other cancerous cell line (TCCSUP, HT-29) and control cells system (CV-1) apoptosis-induced ability, its result is as shown in table 6.

Table 6:

Those skilled in the art are appreciated that the present invention is not limited to special instruction and description above.More properly, scope of the present invention is defined by claim.

Claims

1. one kind suc as formula SARM (SARM) compound shown in the I structure:

X is a key, O, CH ₂, NH, S, Se, PR, NO or NR;

G is O or S;

T be OH, OR ,-NHCOCH ₃Or NHCOR;

R ₁Be CH ₃, CH ₂F, CHF ₂, CF ₃, CH ₂CH ₃Or CF ₂CF ₃

Or

Z is NO ₂, CN, COR, COOH or CONHR;

Y is CF ₃, F, Br, Cl, I, CN or SnR ₃

Q is SCN, NCS, OCN or NCO;

N is the integer of 1-4; With

M is the integer of 1-3.

2. one kind suc as formula SARM (SARM) compound shown in the I structure:

X is a key, O, CH ₂, NH, S, Se, PR, NO or NR;

G is O or S;

T be OH, OR ,-NHCOCH ₃Or NHCOR;

R ₁Be CH ₃, CH ₂F, CHF ₂, CF ₃, CH ₂CH ₃Or CF ₂CF ₃

Or

Z is NO ₂, CN, COR, COOH or CONHR;

Y is CF ₃, F, Br, Cl, I, CN or SnR ₃

Q is SCN, NCS, OCN or NCO;

N is the integer of 1-4; With

M is the integer of 1-3;

Or its analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicament production, N-oxide compound, hydrate, perhaps their arbitrary combination.

3. compound according to claim 1, wherein G is O.

4. compound according to claim 1, wherein T is OH.

5. compound according to claim 1, wherein R ₁Be CH ₃

6. compound according to claim 1, wherein X is O.

7. compound according to claim 1, wherein Z is NO ₂

8. compound according to claim 1, wherein Z is CN.

9. compound according to claim 1, wherein Y is CF ₃

10. compound according to claim 1, wherein Q is NCS.

11. compound according to claim 1, wherein G is O, and T is OH, R ₁Be CH ₃, X is O, Z is NO ₂, Y is CF ₃, Q is NCS.

12. compound according to claim 1, wherein said compound is an androgen receptor antagonists.

13. compound according to claim 1, wherein said compound is irreversibly in conjunction with androgen receptor.

14. compound according to claim 1, wherein said compound is an androgen receptor antagonists, and it is irreversibly in conjunction with androgen receptor.

15. one kind suc as formula SARM (SARM) compound shown in the II structure:

Wherein, X is a key, O, CH ₂, NH, S, Se, PR, NO or NR;

G is O or S;

R ₁Be CH ₃, CH ₂F, CHF ₂, CF ₃, CH ₂CH ₃Or CF ₂CF ₃

T be OH, OR ,-NHCOCH ₃Or NHCOR;

A is selected from following ring:

With

B is selected from following ring:

With

Wherein A and B can not be phenyl ring simultaneously;

Z is NO ₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF ₃, F, I, Br, Cl, CN, CR ₃Or SnR ₃

Q ₁Be NCS, SCN, NCO or OCN;

Q ₂Be H, alkyl, halogen, CF ₃, CN, CR ₃, SnR ₃, NR ₂, NHCOCH ₃, NHCOCF ₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH ₃, NHCSCF ₃, NHCSR, NHSO ₂CH ₃, NHSO ₂R, OR, COR, OCOR, OSO ₂R, SO ₂R, SR,

Q ₃And Q ₄Independently be respectively H, alkyl, halogen, CF ₃, CN, CR ₃, SnR ₃, NR ₂, NHCOCH3, NHCOCF ₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH ₃, NHCSCF ₃, NHCSR, NHSO ₂CH ₃, NHSO ₂R, OR, COR, OCOR, OSO ₂R, SO ₂R, SR;

W ₁Be O, NH, NR, NO or S; With

W ₂Be N or NO.

16. one kind suc as formula SARM (SARM) compound shown in the II structure:

Wherein, X is a key, O, CH ₂, NH, S, Se, PR, NO or NR;

G is O or S;

R ₁Be CH ₃, CH ₂F, CHF ₂, CF ₃, CH ₂CH ₃Or CF ₂CF ₃

T be OH, OR ,-NHCOCH ₃Or NHCOR;

A is selected from following ring:

With

B is selected from following ring:

With

Wherein A and B can not be phenyl ring simultaneously;

Z is NO ₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF ₃, F, I, Br, Cl, CN, CR ₃Or SnR ₃

Q ₁Be NCS, SCN, NCO or OCN;

Q ₃And Q ₄Independently be respectively H, alkyl, halogen, CF ₃, CN, CR ₃, SnR ₃, NR ₂, NHCOCH3, NHCOCF ₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH ₃, NHCSCF ₃, NHCSR, NHSO ₂CH ₃, NHSO ₂R, OR, COR, OCOR, OSO ₂R, SO ₂R or SR;

W ₁Be O, NH, NR, NO or S; With

W ₂Be N or NO;

Or its analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicament production, N-oxide compound or hydrate, perhaps their arbitrary combination.

17. compound according to claim 15, wherein G is O.

18. compound according to claim 15, wherein T is OH.

19. compound according to claim 15, wherein R ₁Be CH ₃

20. compound according to claim 15, wherein X is O.

21. compound according to claim 15, wherein Z is NO ₂

22. compound according to claim 15, wherein Z is CN.

23. compound according to claim 15, wherein Y is CF ₃

24. compound according to claim 15, wherein Q ₁Be NCS.

25. compound according to claim 15, wherein G is O, and T is OH, R ₁Be CH ₃, X is O, Z is NO ₂, Y is CF ₃, Q is NCS.

26. compound according to claim 15, wherein said compound is an androgen receptor antagonists.

27. compound according to claim 15, wherein said compound is irreversibly in conjunction with androgen receptor.

28. compound according to claim 15, wherein said compound is an androgen receptor antagonists, and it is irreversibly in conjunction with androgen receptor.

29. SARM (SARM) compound shown in the formula III structure:

Wherein, X is a key, O, CH ₂, NH, S, Se, PR, NO or NR;

G is O or S;

T be OH, OR ,-NHCOCH ₃Or NHCOR;

Z is NO ₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF ₃, F, I, Br, Cl, CN, CR ₃Or SnR ₃

Q is SCN, NCS, OCN or NCO;

R ₁Be CH ₃, CH ₂F, CHF ₂, CF ₃, CH ₂CH ₃Or CF ₂CF ₃

30. SARM (SARM) compound shown in the formula III structure:

Wherein, X is a key, O, CH ₂, NH, S, Se, PR, NO or NR;

G is O or S;

T be OH, OR ,-NHCOCH ₃Or NHCOR;

Z is NO ₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF ₃, F, I, Br, Cl, CN, CR ₃Or SnR ₃

Q is SCN, NCS, OCN or NCO;

R ₁Be CH ₃, CH ₂F, CHF ₂, CF ₃, CH ₂CH ₃Or CF ₂CF ₃

31. compound according to claim 29, wherein G is O.

32. compound according to claim 29, wherein T is OH.

33. compound according to claim 29, wherein R ₁Be CH ₃

34. compound according to claim 29, wherein X is O.

35. compound according to claim 29, wherein Z is NO ₂

36. compound according to claim 29, wherein Z is CN.

37. compound according to claim 29, wherein Y is CF ₃

38. compound according to claim 29, wherein Q is NCS.

39. compound according to claim 29, wherein G is O, and T is OH, R ₁Be CH ₃, X is O, Z is NO ₂, Y is CF ₃, Q is NCS.

40. compound according to claim 29, wherein said compound is an androgen receptor antagonists.

41. compound according to claim 29, wherein said compound is irreversibly in conjunction with androgen receptor.

42. compound according to claim 29, wherein said compound is an androgen receptor antagonists, and it is irreversibly in conjunction with androgen receptor.

43. compound according to claim 29, shown in the V structure:

44. composition, comprise claim 1,15,29 or 43 described SARM compounds and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination; And suitable carriers or thinner.

45. pharmaceutical composition, the claim 1,15,29 or 43 described SARM compounds and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination that comprise effective dose; And pharmaceutically acceptable carrier, thinner or salt.

46. a SARM compound is in conjunction with the method for androgen receptor, comprise following steps: with SARM effectively in conjunction with the amount of androgen receptor with the SARM compound described in the claim 1,15,29 or 43 and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination contacts with androgen receptor.

47. the method for a SARM compound irreversible fixation androgen receptor, comprise following steps: with the SARM compound described in the claim 1,15,29 or 43 and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination contacts with androgen receptor with the amount of the effective irreversible fixation androgen receptor of SARM.

48. alkylating method of androgen receptor, comprise following steps: with the SARM compound described in the claim 1,15,29 or 43 and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination contacts with androgen receptor with the amount of effective alkylation androgen receptor.

49. one kind is suppressed spermatogenetic method in patient's body, comprise following steps: to suppress spermatogenetic significant quantity with the SARM compound described in the claim 1,15,29 or 43 and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination contacts with androgen receptor.

50. method of contraception in the male patient body, comprise following steps: to suppress spermatogenetic significant quantity with the SARM compound described in the claim 1,15,29 or 43 and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination uses for described patient, produces the effect of contraception thus in described patient's body.

51. the method for a hormonotherapy, comprise following steps: to change significant quantity that male sex hormone relies on illness with the SARM compound described in the claim 1,15,29 or 43 and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination contacts with patient's androgen receptor.

52. hormone replacement therapy method, comprise following steps: to change significant quantity that male sex hormone relies on illness with the SARM compound described in the claim 1,15,29 or 43 and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination contacts with patient's androgen receptor.

53. method of preventing patient's prostate cancer, comprise following steps: with the SARM compound described in the claim 1,15,29 or 43 and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination contacts with patient's androgen receptor with the significant quantity of preventing described patient's prostate cancer.

54. method for the treatment of the hormone associated conditions, comprise following steps: rely on significant quantity that illness changes with the SARM compound described in the claim 1,15,29 or 43 and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound to cause hormone, perhaps their arbitrary combination is used to described patient.

55. method for the treatment of patient's prostate cancer, comprise following steps: with the SARM compound described in the claim 1,15,29 or 43 and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination is used to described patient with the significant quantity for the treatment of described patient's prostate cancer.

56. method that delays the prostate cancer progress of patients with prostate cancer, comprise following steps: with the SARM compound described in the claim 1,15,29 or 43 and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination is used to described patient with the significant quantity that delays described patient's prostate cancer progress.

57. method of preventing the prostate cancer recurrence of patients with prostate cancer, comprise following steps: with the SARM compound described in the claim 1,15,29 or 43 and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination is used to described patient with the significant quantity of preventing the recurrence of described patient's prostate cancer.

58. method for the treatment of the prostate cancer recurrence of patients with prostate cancer, comprise following steps: with the SARM compound described in the claim 1,15,29 or 43 and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination is used to described patient with the significant quantity for the treatment of the recurrence of described patient's prostate cancer.

59. method for the treatment of xerophthalmia patients dry eyes illness, comprise following steps: with the SARM compound described in the claim 1,15,29 or 43 and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination is used to described patient with the significant quantity for the treatment of described patient's xeropthalmus.

60. method of preventing patient's dry eyes illness, comprise following steps: with the SARM compound described in the claim 1,15,29 or 43 and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination is used to described patient with the significant quantity of prevention patient xeropthalmus.

61. method of inducing the prostate cancer cell apoptosis, comprise following steps: with induce described cancer cell-apoptosis effectively amount with claim 1,15,29 or 43 SARM compound and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, perhaps their arbitrary combination and described cells contacting.

62. method for preparing suc as formula the SARM shown in the I (SARM) compound:

Wherein X is O, NH, S, Se, PR or NR;

G is O or S;

T be OH, OR ,-NHCOCH ₃Or NHCOR;

R ₁Be CH ₃, CH ₂F, CHF ₂, CF ₃, CH ₂CH ₃Or CF ₂CF ₃

Or

Z is NO ₂, CN, COR, COOH or CONHR;

Y is CF ₃, F, Br, Cl, I, CN or SnR ₃

Q is SCN, NCS, OCN or NCO;

N is the integer of 1-4; With

M is the integer of 1-3;

Described method comprises formula VIII compound

Wherein Z, Y, G, R ₁, T, R ₃As above define with m, L is a leavings group,

Coupling step with formula IX compound:

Wherein Q, X, R ₂As above define with n.

63. according to the described method of claim 62, wherein G is O, T is OH, R ₁Be CH ₃, X is O, Z is NO ₂, Y is CF ₃, and Q is NCS.

64. according to the described method of claim 62, its Chinese style VIII compound is as follows:

A) by the compound of formula XI ring compound open loop preparation formula X

Wherein L, R ₁, G and T as above define, and T ₁Be O or NH; With

B) with the amine of formula XII

65., further comprise the purify step of described formula I compound of the mixture that uses the second alcohol and water according to the described method of claim 62.

66., further comprise the step that SARM (SARM) compound changes into its analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, hydrate or their arbitrary combination according to the described method of claim 62.

67. the method for SARM (SARM) compound shown in the preparation formula II structure:

Wherein, X is O, NH, S, Se, PR or NR;

G is O or S;

R ₁Be CH ₃, CH ₂F, CHF ₂, CF ₃, CH ₂CH ₃Or CF ₂CF ₃

T be OH, OR ,-NHCOCH ₃Or NHCOR;

A is selected from following ring compound:

With

B is selected from following ring compound:

With

Wherein A and B can not be phenyl ring simultaneously;

Z is NO ₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF ₃, F, I, Br, Cl, CN, CR ₃Or SnR ₃

Q ₁Be NCS, SCN, NCO or OCN;

Q ₃And Q ₄Be independently H, alkyl, halogen, CF separately ₃, CN, CR ₃, SnR ₃, NR ₂, NHCOCH ₃, NHCOCF ₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH ₃, NHCSCF ₃, NHCSR, NHSO ₂CH ₃, NHSO ₂R, OR, COR, OCOR, OSO ₂R, SO ₂R or SR;

W ₁Be O, NH, NR, NO or S; With

W ₂Be N or NO;

Described method comprises formula XIII compound

Wherein A, G, R ₁As above define with T, and L is leavings group,

With formula HX-B compound link coupled step, wherein B and X as above define.

68. according to the described method of claim 67, wherein G is O, T is OH, R ₁Be CH ₃, X is O, Z is NO ₂, Y is CF ₃, and Q ₁Be NCS.

69. according to the described method of claim 67, the amine of its Chinese style XIII is prepared as follows:

A) by the compound of formula XI ring compound open loop preparation formula X

Wherein L, R ₁, G and T as above define, and T ₁Be O or NH; With

B) formula A-NH ₂Amine, wherein A as above defines, in the presence of coupling agent with formula X compound reaction, with preparation formula XIII compound.

70., further comprise the purify step of described formula II compound of the mixture that uses the second alcohol and water according to the described method of claim 67.

71., further comprise the step that SARM (SARM) compound changes into its analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, hydrate or their arbitrary combination according to the described method of claim 67.

72. method for preparing the SARM shown in the formula III structure (SARM) compound:

Wherein, X is O, NH, S, Se, PR or NR;

G is O or S;

T be OH, OR ,-NHCOCH ₃Or NHCOR;

Z is NO ₂, CN, COOH, COR, NHCOR or CONHR;

Y is CF ₃, F, I, Br, Cl, CN, CR ₃Or SnR ₃

Q is SCN, NCS, OCN or NCO;

R ₁Be CH ₃, CH ₂F, CHF ₂, CF ₃, CH ₂CH ₃Or CF ₂CF ₃

Described method comprises formula XIV compound:

Wherein Z, Y, G, R ₁As above define with T, L is a leavings group,

With formula XV compound link coupled step:

Wherein Q, X as above define.

73. according to the described method of claim 72, wherein G is O, T is OH, R ₁Be CH ₃, X is O, Z is NO ₂, Y is CF ₃, and Q is NCS.

74. according to the described method of claim 72, its Chinese style XIV compound is as follows:

A) by the compound of formula XI ring compound open loop preparation formula X

Wherein L, R ₁As above define with T, G is O, and T ₁Be O or NH; With

B) amine of formula XVI

In the presence of coupling agent, react, with preparation formula XIV compound with formula X compound.

75., further comprise the purify step of described formula III compound of the mixture that uses the second alcohol and water according to the described method of claim 72.

76., further comprise the step that SARM (SARM) compound changes into its analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicament production, hydrate or N-oxide compound, hydrate or their arbitrary combination according to the described method of claim 72.

77. according to the described method of claim 72, wherein said androgen receptor modifier (SARM) is represented by formula V: