CN108350024A

CN108350024A - A kind of substituted steroid compound and its application

Info

Publication number: CN108350024A
Application number: CN201680065029.5A
Authority: CN
Inventors: 王义汉; 任兴业
Original assignee: Shenzhen Targetrx Inc
Current assignee: Shenzhen Targetrx Inc
Priority date: 2016-02-19
Filing date: 2016-12-29
Publication date: 2018-07-31
Anticipated expiration: 2036-12-29
Also published as: CN112851741B; CN108350024B; CN112851741A; WO2017140183A1

Abstract

The present invention provides a kind of substituted steroid compounds and its application.Specifically, substituted steroid compound of the present invention is such as formula（I）Shown in steroidal compounds or its crystal form, pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate or solvated compounds.Substituted steroid compound disclosed by the invention and composition comprising the compound are to CYP17 enzymes and androgen receptor（AR）With excellent inhibition, while there is better pharmacokinetic parameter characteristic, the drug concentration of compound in animal body can be improved, to improve curative effect of medication and safety.

Description

A kind of substituted steroid compound and its application

Technical field

The invention belongs to field of medicaments.Specifically, the present invention relates to steroid compounds and application thereof, more specifically, it is related to steroid compound and its as CYP17 enzyme irreversible inhibitor and androgen receptor (AR) antagonist, can be used for treating and preventing and CYP17 enzyme and androgen receptor (AR) related disease.

Background technique

Prostate cancer (prostate cancer, English are abbreviated as PCa) is the common malignant tumour of male reproductive system.There are 903500 prostate cancer new cases and 258400 prostate cancer deaths in the whole world in 2008.Wherein prostate cancer new cases account for the 14% of all tumour new cases of male, rank male tumor new cases the 2nd；Prostate cancer death accounts for the 6% of male cancer deaths case, ranks male cancer deaths case the 6th.Prostate cancer death accounts for the 9% of male cancer deaths case, is only second to lung cancer, ranks male cancer deaths case the 2nd.As environmental pollution in recent years aggravates, pace of population aging accelerates and the reasons such as the change of people's living and diet mode, the disease incidence and death rate rapid increase of prostate cancer, has become one of the important diseases for influencing Chinese male health.

Influence of the androgen to prostate carcinoma cell growth is by androgen receptor (androgen receptor, AR) signal path mediates, patient's body prostate-specific antigen (Prostate Specific Antigen is observed clinically by the variation of AR signal, PSA) horizontal, thus the development situation of diagnosis and treatment patient's prostate cancer.Traditional castration cannot thoroughly inhibit the generation of androgen or the expression of androgen receptor target gene, when the overexpression of the biological enzyme of synthetic androgen, just will increase the level of androgen in tumour.

Cytochrome pathways c17 (CYP17) has expression in testis, adrenal gland and normal prostate tissue, while it is also expressed in prostate gland cancer cell.17 α-hydroxylase and C17,20- lyases in CYP17 are the key enzymes in androgen biosynthesis, and steroids progestational hormone and pregnenolone can be promoted to be separately converted to C19 androstenedione and dehydroepiandros-sterone, and the two converts testosterone and dihydrotestosterone in turn again.

Based on the studies above, the work for preventing and treating prostate cancer is very urgent, and researchs and develops the important directions that CYP17 enzyme inhibitor is Drug Therapies of Prostate Cancer.As novel C YP17 enzyme inhibitor, Abiraterone acetate is developed by Centocor Ortho company for treating prostate cancer.Abiraterone acetate is ratified to list in 28 Nikkei U.S. FDA April in 2011, is combined treatment castration-resistant prostate cancer, trade name Zytiga with prednisone.On July 28th, 2011, Zytiga obtain Her Majesty the Queen in right of Canada as represented by the minister of Healt's approval.For patients with prostate cancer, hormone testosterone can stimulate the growth of tumour, castration including drug or operative treatment can reduce the generation of testosterone or block the effect of testosterone, but this treatment can not inhibit other body parts to generate androgen, and prostate cancer can still continue to increase.

Summary of the invention

Against the above technical problems, the invention discloses a kind of substituted steroid compound and compositions comprising the compound and application thereof, it is with better CYP17 enzyme and androgen receptor (AR) inhibitory activity and/or has more preferable pharmacodynamics/pharmacokinetics performance, can be used for treating, prevents and alleviate by the disease to CYP17 enzyme or androgen receptor (AR) mediation.

In this regard, the technical solution of the present invention is as follows:

A kind of substituted steroid compound, the steroidal compounds as shown in formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds,

In formula:

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹、R²²、R²³It is independently selected from the group being made of " hydrogen (H), deuterium (D) "；

X¹、X²It is independently selected from by " hydrogen (H), deuterium (D), methyl, CH₂D、CHD₂、CD₃、CH₂CH₃、CHDCH₃、CHDCH₂D、CHDCHD₂、CHDCD₃、CD₂CH₃、CD₂CH₂D、CD₂CHD₂、CD₂CD₃" composition group；

Y is selected from " hydrogen (H), deuterium (D), hydroxyl, acetyl group, one or many deuterated acetyl group "；

And its physiologically acceptable salt, prodrug, metabolin, solvate, tautomer and stereoisomer, the mixture formed including these compounds with all proportions.

In another preferred example, R¹、R²、R³、R⁴、R⁵From independently being deuterium or hydrogen.

In another preferred example, Y is selected from hydrogen, deuterium, hydroxyl, one or many deuterated acetyl group.

In another preferred example, X¹、X²For methyl deuterated three times.

In another preferred example, the compounds of this invention is selected from the substituted steroid compound or its pharmaceutically acceptable salt in the following group, but is not limited to following compound:

It is selected in example another, the compound does not include non-deuterated compound.

As a further improvement of the present invention, deuterium isotopic content of the deuterium in deuterated position is at least greater than natural deuterium isotopic content 0.015%, is preferably greater than 30%, even more preferably greater than 50%, even more preferably greater than 75%, even more preferably greater than 95%, even more preferably greater than 99%.

Specifically, R in the present invention¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹、R²²、R²³And X¹、X²Deuterium isotopic content is at least 5% in each deuterated position, it is preferably greater than 10%, even more preferably greater than 15%, even more preferably greater than 20%, even more preferably greater than 25%, even more preferably greater than 30%, even more preferably greater than 35%, even more preferably greater than 40%, even more preferably greater than 45%, even more preferably greater than 50%, even more preferably greater than 55%, even more preferably greater than 60%, even more preferably greater than 65%, even more preferably greater than 70%, even more preferably greater than 75%, even more preferably greater than 80%, even more preferably greater than 85%, even more preferably greater than 90%, even more preferably greater than 95%, even more preferably greater than 99%.

It is selected in example another, the R of compound in formula (I)¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、 R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹、R²²、R²³, at least one of which R contains deuterium, more preferably two R contain deuterium, more preferably three R contain deuterium, more preferably four R contain deuterium, more preferably five R contain deuterium, more preferably six R contain deuterium, more preferably seven R contain deuterium, more preferably eight R contain deuterium, more preferably nine R contain deuterium, more preferably ten R contain deuterium, more preferably 11 R contain deuterium, more preferably 12 R contain deuterium, more preferably 13 R contain deuterium, more preferably 14 R contain deuterium, more preferably 15 R contain deuterium, more preferably 16 R contain deuterium, more preferably 17 R contain deuterium, more preferably 18 R contain deuterium, more preferably 19 R contain deuterium, more preferably 20 R contain deuterium, more preferably 21 R contain deuterium, more preferably 22 R contain deuterium, more preferably 23 R contain deuterium.

As a further improvement of the present invention, by pharmaceutically acceptable carrier and the steroid compound that as described above replaces, or its crystal form, pharmaceutically acceptable salt, prodrug, metabolin, stereoisomer, isotopic variations hydrate or solvate are mixed, to form pharmaceutical composition.

The invention also discloses a kind of pharmaceutical compositions, its pharmaceutical composition for containing pharmaceutically acceptable carrier and the steroid compound replaced as described above or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, stereoisomer, prodrug or isotopic variations.

The invention also includes the compounds of isotope labelling, are equal to original chemical and are disclosed.The example that the compound of the present invention isotope can be classified as includes hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine isotope, respectively such as²H,³H,¹³C,¹⁴C,¹⁵N,¹⁷O,¹⁸O,³¹P,³²P,³⁵S,¹⁸F and³⁶Cl.Compound or enantiomer in the present invention, diastereomer, isomers or pharmaceutically acceptable salt or solvate, wherein being within the scope of the present invention containing the isotope of above compound or other other isotope atoms.Certain compound isotopically labelleds in the present invention, such as³H and¹⁴The radioactive isotope of C is also useful in the experiment of the Tissue distribution of drug and substrate wherein.Tritium, i.e.,³H and carbon-14, i.e.,¹⁴C, their preparation and detection are easier, and are the first choices in isotope.The compound of isotope labelling can use general method that can be prepared by replacing with non isotopic reagent with the isotope labeling reagent being easy to get with the scheme in example.

It as a further improvement of the present invention, also include other treatment drug, the therapeutic agent is the drug of cancer, cell proliferation disorders, inflammation, infection, immunity disease, organ transplant, viral disease, cardiovascular disease or metabolic disease.

Pharmaceutical composition of the invention includes the compounds of this invention or its pharmacologically acceptable salt and pharmacologically acceptable excipient or carrier within the scope of safe and effective amount.Wherein " safe and effective amount " refers to: the amount of compound is enough to be obviously improved the state of an illness, and is unlikely to generate serious side effect.In general, pharmaceutical composition contains 1-2000mg the compounds of this invention/agent, more preferably, contain 10-1000mg the compounds of this invention/agent.Preferably, described is " one " for a capsule or tablet.

The invention also discloses the steroid compounds replaced as described above, or the purposes of its crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds, it is used to prepare treatment, prevention and alleviates by the pharmaceutical composition of the disease to CYP17 enzyme and androgen receptor (AR) mediation.

Since the compounds of this invention has excellent inhibitory activity to CYP17 enzyme and androgen receptor (AR), therefore the compounds of this invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and containing the pharmaceutical composition that the compounds of this invention is main active can be used for treating, prevent and alleviates the disease by mediating to CYP17 enzyme and androgen receptor (AR).According to the prior art, the compounds of this invention can be used for treating following disease: prostate cancer, benign prostate hyperplasia, hirsutism, alopecia, anorexia nervosa, breast cancer and male gonad hyperfunction etc..

The invention has the benefit that

Substituted steroid compound disclosed by the invention and composition comprising the compound are to CYP17 enzyme and male swash Plain receptor (AR) has excellent inhibition, while having better pharmacokinetic parameter characteristic, can be improved the drug concentration of compound in animal body, to improve curative effect of medication and safety；Substituted steroid compound disclosed by the invention and the composition comprising the compound can be used for treating, prevent and alleviate the disease by CYP17 enzyme and androgen receptor (AR) mediation.

Specific embodiment

The present inventor studies discovery, deuterated steroid compound and its pharmaceutically acceptable salt of the invention is compared with not deuterated compound, with equivalent or superior pharmacokinetics and/or pharmacodynamics performance, therefore it is suitable as inhibiting the compound of CYP17 enzyme and androgen receptor (AR), and then is more suitable for the drug of preparation treating cancer and CYP17 enzyme and androgen receptor (AR) related disease.The present invention is completed on this basis.

" pharmaceutical salts " used in this application refer to the derivative of the compound, and wherein parent compound is modified by preparing its hydrochlorate or alkali salt.The example of pharmaceutical salts includes but is not limited to the inorganic acid salt or acylate of alkaline residue such as amine；And the alkali salt or organic salt of acidic residues such as carboxylic acid.Pharmaceutical salts include the conventional non-toxic salts or quaternary ammonium salt of the parent compound for example formed by non-toxic inorganic or organic acid.Pharmaceutical salts of the present invention can be synthesized by the parent compound containing alkalinity or acidic moiety by conventional chemical processes.In general, above-mentioned salt can be prepared as follows: making to react in water or organic solvent or the mixture of the two in free acid or these compounds of alkali form with the appropriate alkali of stoichiometry or acid；In general, non-aqueous media such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile are preferred.P.1418 (1985) disclosure of which is incorporated herein by reference by salt appropriate referring to Remington ' s Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, PA.

For example, the salt of formula (I) compound may be formed: reacting formula (I) compound in following medium with the acid of such as equivalent or alkali, the salt that the medium allows newly to be formed such as Precipitation or separated by being lyophilized.The exemplary hydrochlorate that formula (I) compound can be formed with inorganic acid and/or organic acid includes but is not limited to such as acetate, ascorbate, benzoate, benzene sulfonate, disulfate, biatrate, acid citrate, citrate, esilate, formates, fumarate, gentisate, gluconate, glucosaccharic acid salt, glutamate, hydrochloride, hydrobromate, hydriodate, isonicotinic acid salt, maleate, mesylate, mesylate, nitrate, pantothenate, phosphate, acid phosphate, saccharate, salicylate, succinate, hydrochlorate, tartrate, tosilate, trifluoroacetate, lactate and pamoate (i.e. 1, 1 '-methylene-two (2- hydroxyl-naphthalene -3- formates)).Above-mentioned salt can be formed according to method known to those skilled in the art.

The exemplary alkali salt that formula (I) compound can be formed with inorganic base and/or organic base includes but is not limited to such as ammonium salt；Alkali metal salt, such as sodium salt, lithium salts and sylvite；Alkali salt, such as calcium salt and magnesium salts；The salt formed with organic base, the organic base is such as benzyl star (benzathine), dicyclohexylamine, 2- amino -2- (hydroxymethyl) propyl- 1, (trishydroxymethylaminomethane breathes out amine (hydrabamines) (such as N, N- bis- (dehydrogenation rosin-base) ethylenediamine), N- methyl-D-glucosamine, N- methyl D-imidazoles diamides and tert-butylamine to 3- glycol；The salt formed with amino acid (such as arginine and lysine)；With by using following reagent with to Basic nitrogen-containing groups carry out it is quaternized and formed salt, the reagent is such as low alkyl group halogen (such as methyl chloride, methyl bromide, methyl iodide, ethyl chloride, bromic ether, ethyl iodide, propyl chloride, propyl bromide, propyl iodide, butyl chloride, butyl bromide and butyl iodide), dialkyl sulfate (such as dimethyl suflfate, dithyl sulfate, dibutyl sulfate and diamyl sulfates), long chain halide (such as decyl chloride, decyl bromide, iododecane, lauryl chloride, lauryl bromide, lauryl iodine, myristyl chlorine, nutmeg bromide, myristyl iodine, stearyl chloride, stearic bromide and stearyl iodine) and aralkyl halogen (such as benzyl bromide and phenethyl bromide).Above-mentioned salt can be formed according to method known to those skilled in the art.

Term " solvate " refers to that the compounds of this invention and solvent molecule are coordinated the complex to form special ratios." hydrate " refers to that the compounds of this invention and water carry out the complex of coordination formation.

In addition, the compounds of this invention further includes the prodrug of steroid compound shown in formula (I).Term " prodrug " include itself can be it is with biological activity or inactive, after being taken with method appropriate, it is metabolized or is chemically reacted in human body and changes salt or solution composed by a kind of compound of an accepted way of doing sth (I) or a compound of formula (I).The prodrug includes but is not limited to the forms such as carboxylate, carbonic ester, phosphate, nitrate, sulfuric ester, sulfone ester, sulfoxide esters, amino-compound, carbaminate, azo-compound, phosphamide, glucoside, ether, the acetal of the compound.

" therapeutically effective amount " is intended to include the separate amount of the compounds of this invention or the combined amount or the compounds of this invention of claimed compound and the combined amount for the other active constituents for acting effectively as CYP17 enzyme antagonist or effective treating cancer.

" treatment (treating) " used in this application or " treatment (treatment) " includes the treatment carried out in the mammal especially mankind to morbid state and includes: that (a) prevents the morbid state in mammals and occur, especially when the mammal is susceptible to suffer from the morbid state but not yet make a definite diagnosis suffer from the morbid state when；(b) inhibit the morbid state, that is, prevent its development；And/or (c) alleviate the morbid state, even the morbid state subsides.

The compounds of this invention can be existed containing one or more additional asymmetric carbon atoms by two or more stereoisomeric forms in any ratio.The present invention includes all possible single stereoisomers, their single tautomeric form and their mixture.Diastereoisomer can be separated by routine techniques, such as carry out fractional crystallization, chromatography or HPLC by the stereoisomer mixture to the compounds of this invention or its suitable salt or derivative.The single enantiomter of the compound can also be prepared by corresponding optically pure intermediate or be prepared as follows: being split to corresponding racemic modification using suitable chiral support and (such as pass through HPLC) or when appropriate, fractional crystallization is carried out to diastereomeric salt, the diastereomeric salt is prepared by reacting corresponding racemic modification with suitable optically active acid or alkali.All stereoisomers (in mixture or pure or substantially pure form) of the compounds of this invention are included in the present invention.

The invention also includes a kind of pharmaceutical composition, described pharmaceutical composition includes formula (I) compound or pharmaceutically acceptable salt thereof and one or more non-toxic pharmaceutical carriers and/or diluent and/or auxiliary material (referred to collectively herein as " carrier " material) and optional other active constituents.Formula (I) compound can be preferably suitable for the pharmaceutical compositions of above-mentioned approach by any suitable approach and is administered with effective for desired treatment dosage.For example, the compounds of this invention and composition can be administered orally by the dosage unit preparation form containing conventional pharmaceutical carrier, auxiliary material and medium, mucosa delivery or parenteral (including in intravascular, intravenous, peritonaeum, in subcutaneous, intramuscular, breastbone and infusion techniques) administration.For example, mixture of the pharmaceutical carrier containing mannitol or lactose and microcrystalline cellulose.The mixture can contain other components, such as lubricant (such as magnesium stearate) and disintegrating agent (such as Crospovidone).The carrier mixture can be filled into gelatine capsule or tabletted.

Pharmaceutical active compounds of the present invention can be processed according to conventional pharmaceutical method to prepare the drug for being administered to patient (including the mankind and other mammals).

For oral administration, described pharmaceutical composition can be in the form of the following: such as tablet, capsule, suspension or liquid preparation.It is preferred that described pharmaceutical composition to be prepared into the dosage unit form of the active constituent containing specific quantity.The example of the dosage unit is tablet or capsule.

The chemical combination object amount that is administered and many factors, age, weight, gender and medical condition, disease type, disease severity, administration route and frequency and used particular compound including subject are depended on the dosage regimen that the compounds of this invention and/or composition treat illness.Therefore, the dosage regimen is alterable very big, but standard method can be used routinely to determine.

For therapeutic purposes, usually by reactive compound of the present invention and one or more auxiliary material combinations for being suitable for specified administration route.If oral administration, the compound can then be mixed with the sodium salt and calcium salt of lactose, sucrose, starch powder, alkanoic acid cellulose esters, cellulose alkyl esters, talcum, stearic acid, magnesium stearate, magnesia, phosphoric acid and sulfuric acid, gelatin, Arabic gum, sodium alginate, polyvinyl alcohol and/or polyvinylpyrrolidone, then tabletting or packing are to facilitate administration.Above-mentioned capsule or tablet may include controlled release preparation, and the controlled release preparation can be provided by dispersion of the reactive compound in hydroxypropyl methyl cellulose.

The oil of emulsion containing formula (I) compound can be mutually made of in a known manner principal component.It may include at least one emulsifier and fat or oil or the mixture with fat and oil although the phase can only include emulsifier.Preferably, hydrophilic emulsifier and the lipophilic emulsifier as stabilizer are included in together.Not only comprising oil but also comprising fatty and preferred.In addition, emulsifier (with or without stabilizer) constitutes so-called emulsifying wax and the wax and oil & fat are formed together so-called emulsifying ointment base, the emulsifying ointment base forms the oil dephasing of cream.It include polysorbate60, sorbester p17, cetostearyl alcohol, myristyl alcohol, glycerin monostearate, NaLS or distearin suitable for the emulsifier used in invention formulation and emulsion stabilisers, these substances are used alone or are used together with wax or other materials well known in the art.

Described pharmaceutical composition can undergo conventional manner operation (sterilizing) and/or can contain customary adjuvant (preservative, stabilizer, wetting agent, emulsifier and buffer etc.).Tablet and pill also can be used enteric coating to prepare.The composition also may include auxiliary material, such as wetting agent, sweetener, corrigent and aromatic.

Pharmaceutical composition of the present invention includes formula (I) compound or pharmaceutically acceptable salt thereof and optional other materials, and the other materials are selected from any pharmaceutical carrier, auxiliary material and medium.The selectable present composition includes formula described herein (I) compound or pharmaceutically acceptable salt thereof and pharmaceutical carrier, auxiliary material or medium.

Formula (I) compound is used for treating cancer, such as the cancer dependent on androgen receptor signal transduction.These compounds inhibit the activity of CYP17 enzyme, and the CYP17 enzyme participates in the biosynthesis of androgen.It blocks the enzyme that can inhibit the generation of sexual gland, adrenaline and neoplastic androgenic, and a kind of new selection for treating cancer (breast cancer of such as prostate cancer and estrogen receptor positive) patient dependent on androgen receptor signal transduction is provided.Therefore, the treatment includes giving patient's formula (I) compound or pharmaceutically acceptable salt thereof.

In one embodiment, a kind of method for treating cancer is provided, the method includes giving the mammal formula (I) compound of needs.The method of the embodiment can be used for treating kinds cancer, including but not limited to bladder cancer, breast cancer, colorectal cancer, gastric cancer, head and neck cancer, kidney, liver cancer, lung cancer, oophoroma, pancreas/gallbladder cancer, prostate cancer, thyroid cancer, bone and flesh cancer, rhabdomyosarcoma, malignant fibrous histiocytoma (MFH), fibrosarcoma, spongioblastoma/astrocytoma, melanoma and celiothelioma.

Preferably, the method for the embodiment is for treating a variety of prostate cancers.

Amount and dosage regimen for treating formula (I) compound of particular cancers being administered depend on many factors, age, weight, gender and medical condition, disease type, disease severity, administration route and frequency and used particular compound including subject.Therefore, the dosage regimen is alterable very big, but standard method can be used routinely to determine.About 0.01 to 1500mg/kg weight, preferably from about 0.5 to about 50mg/kg weight and most preferably about 0.1 to the daily dose of 20mg/kg weight can be suitable.The daily dose can be administered by 1-4 times/day.

When treating cancer, chemotherapeutant and/or the combination of other treatments (such as radiotherapy) are tended to be advantageous in that.Second (or third) preparation can have the mechanism of action identical or different with primary treatment agent.It the use of cytotoxic drug combination may be particularly useful, wherein give two or more drugs to work in different ways or in the different cell cycles, and/or two or more of them drug has the toxicity or side effect of overlapping, and/or the drug wherein combined when treating the particular disease states that patient shows respectively has apparent curative effect.

Therefore, formula (I) compound can be with other anticancer therapies for being used for treating cancer or other proliferative diseases Combination is given.The present invention further comprises the purposes of formula (I) compound in the preparation of medicament for cancer treatment, and/or the packaging including the application formula (I) compound and specification, it is combined with other anticancer agents or cytotoxic agent and wherein the compound is used in the treatment for the treatment of cancer.The present invention further comprises the combination of formula (I) compound and one or more of the other medicament in a kit form, such as they are packaged together or are placed in separated packaging and sell together as kit or they are packaged to prepare together.

Other anticancer agents can be selected from one or more below: alkylating agent (including mustargen, alkyl sulfonic ester, nitroso ureas, aziridine derivative and triazenes)；Anti-angiogenic agent (including Matrix Metalloproteinase Inhibitors)；Antimetabolite (including adenosine deaminase inhibitors, antifol, purine analogue and pyrimidine analogue)；Antibiotic or antibody (including monoclonal antibody, CTLA-4 antibody, anthracycline antibiotic)；Aromatase inhibitor；Cell cycle reaction control agent；Enzyme；Farnesyl-protein (farnesyl-protein) inhibitors；Hormone and antihormone agent and steroids (including synthetic analogues, glucocorticoid, estrogen/antiestrogenic (such as SERMs), androgen/antiandrogen, progestational hormone, progesterone receptor agonist and luteinizing principle release agonist and antagonist)；Insulin-like growth factor/insulin-like growth factor receptor system modifier；Integrin signal transduction inhibitor；Kinase inhibitor (including multi-kinase inhibitor and/or Src kinases or Src/abl inhibitor), cell cycle protein dependent kinase (CDK) inhibitor, panHer, Her-1 and Her-2 antibody, VEGF inhibitor (including anti-VEGF antibody), EGFR inhibitor, mitogen-activated protein [MAP] inhibitor, mek inhibitor, Aurora A inhibitor, PDGF inhibitor and other tyrosine kinase inhibitors or serine/threonine kinase inhibitor)；Microtubule disrupting agent, such as ascidian chlorins compound or their analogs and derivatives；Microtubule stabilizer such as taxanes and naturally occurring Epothilones and their synthesis and semi-synthetic analog；Micro-pipe combines and destabilizing agent (including vinca alkaloids)；Topoisomerase enzyme inhibitor；Prenyl-protein inhibitors；Platinum coordination complex；Signal transduction inhibitor；With other preparations as anticancer and cytotoxic agent, such as biological response modifiers, growth factor and immunomodulator.

The preparation method of formula (I) structural compounds of the present invention is described more particularly below, but these specific methods do not form any restrictions to the present invention.Various synthetic methods describing in the present specification or known in the art can also optionally be combined and are easily made by the compounds of this invention, and such combination can be easy to carry out by those skilled in the art in the invention.

Present invention will be further explained below with reference to specific examples.It should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to normal condition, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise parts and percentages are parts by weight and weight percent.

Embodiment 1 prepares 3 β -17- (1H- benzo [d] imidazoles -2-d-1- base) androstane -5,16- dien-3-ols (compound 7)

Step 1:(3 β) -3- (acetoxyl group) -17- chlorine androstane -5,16- diene -16- formaldehyde (compound 2) synthesis.

Under ice bath, n,N-Dimethylformamide (15mL, 192mmol) is slowly dropped in chloroform (45mL) solution of phosphorus oxychloride (15mL, 165mmol) under nitrogen protection.After being added dropwise, chloroform (45mL) solution of Dehydroepiandrosterone Acetate (3.00g, 9.00mmol) is slowly dropped into.It is added dropwise, is warming up to room temperature, back flow reaction 5hrs.Reaction solution is concentrated under reduced pressure, residue is added in ice water, with ether/ethyl acetate (8/2, v/v) mixed extractant solvent, merges organic layer, and with saturated common salt water washing, anhydrous sodium sulfate is dry.Organic layer is concentrated under reduced pressure, concentration fluid column chromatographic purifying obtains 2.10g beige solid, yield: 62.0%.LC-MS (APCI): m/z=377.2 [M+1]⁺。

Step 2:(3 β) -3- (acetoxyl group) -17- (1H- benzo [d] imidazoles -1- base) androstane -5,16- diene -16- formaldehyde (compound 4) synthesis.

At room temperature; by anhydrous N under nitrogen protection; dinethylformamide (10mL) is added to (3 β) -3- (acetoxyl group) -17- chlorine androstane -5; 16- diene -16- formaldehyde (2.10; 5.62mmol), benzimidazole (2.00g, 16.86mmol) and potassium carbonate (2.80g; in mixture 20.2mmol), reaction solution reacts stirring 2.5 hours at 80 DEG C.Reaction solution is cooled to room temperature, and is added in ice water (250mL), solid filtering, washing, and vacuum drying (60 DEG C) obtains crude product, and crude product column chromatographic purifying obtains 2.10g yellow solid, yield: 80%.LC-MS (APCI): m/z=459.3 [M+1]⁺。

Step 3:(3 β) -3- (acetoxyl group) -17- (1H- benzo [d] imidazoles -1- base) androstane -5,16- diene (compound 5) synthesis.

At room temperature, by palladium carbon (10%, 1.2g) it is added to (3 β) -3- (acetoxyl group) -17- (1H- benzo [d] imidazoles -1- base) androstane -5,16- diene -16- formaldehyde (2.10mmol, 4.58mmol) anhydrous benzonitrile (12mL), back flow reaction 24 hours.Reaction solution is cooled to greenhouse, diatomite filtering, and column chromatographic purifying obtains 1.48g yellow solid, yield: 75.0%.LC-MS (APCI): m/z=431.3 [M+1]⁺。

The synthesis of step 4:3 β -17- (1H- benzo [d] imidazoles -1- base) androstane -5,16- dien-3-ols (compound 6).

At room temperature; under nitrogen protection; the methanol solution (10mL) of 10% potassium hydroxide is added to (3 β) -3- (acetoxyl group) -17- (1H- benzo [d] imidazoles -1- base) androstane -5; 16- diene (1.45g; 3.36mmol) methanol solution (20mL), reaction solution be stirred at room temperature reaction 2 hours.It is concentrated under reduced pressure into the reaction solution of about 10mL, is added in ice water (40mL), solid filtering is washed with ice water, and vacuum drying obtains 1.20g buff white solid, yield: 92.9%, purity: 98.64%.LC-MS (APCI): m/z=389.3 [M+1]⁺；¹H NMR(300MHz,CDCl₃) (δ/ppm) 8.14 (s, 1H), 7.66 (dd, J=6.8,1.8Hz, 1H), 7.54 (dd, J=6.9,1.8Hz, 1H), 7.36-7.23 (m, 2H), 6.04 (dd, J=2.8,1.6Hz, 1H), (5.38 d, J=5.0Hz, 1H), 3.46-3.32 (m, 1H), 2.46-2.35 (m, 1H), 2.30-2.17 (m, 3H), 2.16-2.03 (m, 1H), 1.84-1.64 (m, 8H), 1.61-1.41 (m, 2H), 1.16-1.07 (m, 2H), 1.04 (s, 3H), 1.00 (s 3H).

The synthesis of step 5:3 β -17- (1H- benzo [d] imidazoles -2-d-1- base) androstane -5,16- dien-3-ols (compound 7).

Sodium methoxide (90mg, 1.50mmol) is added to the deuterated methanol (CD of -3 β -ol (100mg, 0.25mmol) of 17- (1H- benzo [d] imidazoles -1- base) androstane -5,16- diene₃OD-d₄, 5mL), 100 DEG C of tube sealing reactions are overnight under nitrogen protection.Aggravate water (10mL) quenching reaction, (10mL x 4) is extracted with dichloromethane, organic phase is washed with saturated salt solution (15mL), anhydrous sodium sulfate is dry, it is concentrated under reduced pressure, concentrate carries out post separation, obtains buff white solid 50mg, yield: 50.0%, purity: 99.16%.LC-MS (APCI): m/z=390.0 (M+1)；¹H NMR(300MHz,MeOD-d)(δ/ppm)8.19(s,0.04H),7.76– (7.65 m, 1H), 7.59 (dd, J=6.8,1.8Hz 1H), 7.40-7.26 (m, 2H), 6.09 (dd, J=3.0,1.6Hz, 1H), 5.43 (d, J=5.0Hz, 1H), 3.50-3.37 (m, 1H), 2.52-2.41 (m, 1H), 2.35-2.22 (m, 3H), 2.21-2.09 (m, 1H), 1.92-1.69 (m, 8H), 1.66-1.43 (m, 2H), 1.22-1.12 (m, 2H), 1.09 (s, 3H), 1.05 (s, 3H).

Embodiment 2 prepares 3 β -17- (1H- benzo [d] imidazoles -5,6,7-d₃- 1- base) (the change of androstane -5,16- dien-3-ols Close object 13)

At room temperature, anhydrous dimethyl sulfoxide (6mL) liquid is added to -3 β -ol (300mg, 0.75mmol) of 17- iodine androstane -5,16- diene by nitrogen protection, 1H- benzo [d] imidazoles -4,5, and 6,7-d₄In the mixture of (110mg, 0.90mmol), L-PROLINE (35mg, 0.3mmol), cuprous iodide (30mg, 0.15mmol) and potassium carbonate (259mg, 1.87mmol), reaction solution is stayed overnight at 120 DEG C.It is cooled to room temperature, add water (25mL) quenching reaction, diatomite filtering, filtrate are extracted with ethyl acetate (30mL x 3), merge organic layer, the saline solution (30mL) of organic layer saturation washs, anhydrous sodium sulfate is dry, and organic layer is concentrated under reduced pressure, and concentration fluid column chromatographic purifying obtains 80mg white solid, yield: 27.2%, purity: 99.37%.LC-MS (APCI): m/z=393.0 [M+1]⁺；¹H NMR (300MHz, MeOD-d) (δ/ppm) 8.18 (s, 1H), 6.08 (dd, J=3.1,1.7Hz, 1H), 5.42 (d, J=5.1Hz, 1H), 3.43 (m, 1H), 2.46 (m, 1H), 2.27 (m, 3H), 2.14 (m, 1H), 1.80 (m, 8H), 1.53 (m, 2H), 1.14 (m, 2H), 1.08 (s, 3H), 1.04 (s, 3H).

Embodiment 3 prepares 3 β -17- (1H- benzo [d] imidazoles -4,5,6,7-d₄- 1- base) (the change of androstane -5,16- dien-3-ols Close object 15)

Embodiment 4 prepares 17- (1H- benzo [d] imidazoles -2-d-1- base) androstane -5,16- diene -3- ketone (compound 16)

At room temperature; by under nitrogen protection by 17- (1H- benzo [d] imidazoles -2-d-1- base) androstane -5; -3 β -ol (130mg of 16- diene; 0.33mmol); the mixture of dry toluene (13mL) and N- methyl -4- piperidones (0.5mL) is added in the reflux unit with water segregator, and mixture was at return stirring 1 hour (about steaming the toluene of 2mL).It adds aluminium isopropoxide (205mg, 1.05mmol), reaction solution is stirred to react overnight under reflux.It is cooled to greenhouse, the water of 20mL and the ethyl acetate quenching reaction of 20mL is added, is filtered, filtrate is extracted with ethyl acetate (20mL x 3).Merge organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, and organic layer is concentrated under reduced pressure, and concentration fluid column chromatographic purifying obtains 100mg beige solid, yield: 76.9%, purity: 97.73.LC-MS (APCI): m/z=388.2 (M+1)；¹H NMR (300MHz, MeOD-d) (δ/ppm) 8.18 (s, 0.05H), 7.70 (dd, J=6.7,1.9Hz, 1H), 7.58 (dd, J=6.8,1.8Hz, 1H), 7.40-7.23 (m, 2H), 6.08 (dd, J=3.1,1.7Hz, 1H), 5.75 (s, 1H), 2.63-2.18 (m, 6H), 2.12-1.89 (m, 3H), 1.87-1.53 (m, 6H), (1.28 s, 3H), 1.25-1.11 (m, 2H), 1.07 (s, 3H).

Embodiment 5 prepares 17- (1H- benzo [d] imidazoles -5,6,7-d3-1- base) androstane -5,16- diene -3- ketone (chemical combination Object 17)

At room temperature, by under nitrogen protection by 17- (1H- benzo [d] imidazoles -4,5,6,7-d₄- 1- base) androstane -5, -3 β -ol (36mg of 16- diene, 0.09mmol), the mixture of dry toluene (4mL) and N- methyl -4- piperidones (0.14mL) is added in the reflux unit with water segregator, and mixture was at return stirring 1 hour (about steaming the toluene of 0.5mL).It adds aluminium isopropoxide (60mg, 0.28mmol), reaction solution is stirred to react overnight under reflux.It is cooled to greenhouse, the water of 20mL and the ethyl acetate quenching reaction of 20mL is added, is filtered, filtrate is extracted with ethyl acetate (20mL x 3).Merge organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, and organic layer is concentrated under reduced pressure, and concentration fluid column chromatographic purifying obtains 26mg beige solid, yield: 72.2%, purity: 93.02%.LC-MS (APCI): m/z=391.2 (M+1)；¹H NMR(300MHz,DMSO-d₆)(δ/ppm)8.25(s,1H),6.05(s,1H),5.66(s,1H),2.44–1.52(m,15H),1.18(s,3H),1.08(M,2H),0.98(s,3H)。

Embodiment 6 prepares 17- (1H- benzo [d] imidazoles -4,5,6,7-d₄- 1- base) (the change of androstane -5,16- diene -3- ketone Close object 18)

At room temperature, by under nitrogen protection by 17- (1H- benzo [d] imidazoles -5,6,7-d₃- 1- base) androstane -5, -3 β -ol (140mg of 16- diene, 0.36mmol), the mixture of dry toluene (14mL) and N- methyl -4- piperidones (0.54mL) is added in the reflux unit with water segregator, and mixture was at return stirring 1 hour (about steaming the toluene of 3mL).It adds aluminium isopropoxide (230mg, 1.09mmol), reaction solution is stirred to react overnight under reflux.It is cooled to greenhouse, the water of 20mL and the ethyl acetate quenching reaction of 20mL is added, is filtered, filtrate is extracted with ethyl acetate (20mL x 3).Merge organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, and organic layer is concentrated under reduced pressure, and concentration fluid column chromatographic purifying obtains 29mg beige solid, yield: 20.7%, purity: 94.44%.LC-MS (APCI): m/z=390.3 (M+1)；¹H NMR(300MHz,CDCl₃)(δ/ppm)7.96(s,1H),7.83(s,1H),5.99(s,1H),5.78(s,1H),2.41(m,5H),2.01(m,2H),1.92–1.63(m,8H),1.24(s,3H),1.19–1.09(m,2H),1.05(s,3H)。

Biological activity test

(1) CYP17 external test.

The external CYP17 inhibitory activity of the compound discharges measurement (AARA) to evaluate, using complete P450c17- expression E.coli as enzyme source using quick acetic acid.Including using [21-3H] -17 Alpha-hydroxy pregnenolone to measure CYP17 activity as substrate and by way of a large amount of tritiated acetic acid, during the C-21 side chain cleavage of substrate.IC50 value directly obtains (Grigoryev etc., Br.J.Cancer, 1999,81,622-630) from the invariance curve of suppression percentage and inhibition concentration more than proper range.Minimum value experiment of each compound in five various concentrations.Three parts of measurement, and IC₅₀Value takes the average value tested three times, wherein A indicates IC₅₀< 0.1 μM, B indicates 0.1 μM≤IC₅₀≤ 0.5 μM, C indicates IC₅₀> 0.5 μM (as shown in table 1 below).

(2) inhibiting effect of cell PSA protein secretion.

Experimental procedure: 1. replace original culture medium with the culture medium of the FBS of Stripped containing 10%Charcoal, keep cell 24 hours hungry in culture bottle；2. vitellophag counts, by LNcaP cell inoculation into 96 orifice plates, 10,000/well, and overnight incubation；3. DHT and compound are added in existing culture medium according to setting concentration, the final concentration of 1nM of DHT, compound initial concentration is 50000nM, 5 times of dilutions, 8 concentration gradients, culture 48 hours；4. collecting cells and supernatant, PSA protein level is detected according to ELISA kit specification.According to the inhibiting rate of each concentration, IC is calculated with GraphPad Prism₅₀, wherein A indicates IC₅₀< 0.1 μM, B indicates 0.1 μM≤IC₅₀≤ 0.5 μM, C indicates IC₅₀> 0.5 μM (as shown in table 1 below)

The kinase inhibitory activity analytical table of the substituted steroid compound of 1 Examples 1 to 6 of table

Embodiment number	CYP17 enzyme IC₅₀(μM)	PSA IC₅₀(μM)
Galeterone	B	-
Embodiment 1	B	-
Embodiment 2	A	-
Embodiment 3	A	-
Galeterone metabolin	C	C
Embodiment 4	B	B
Embodiment 5	B	C
Embodiment 6	B	-

As shown in table 1, the compounds of this invention is compared with Galeterone, the CYP17 enzyme inhibition activity of embodiment 1 is suitable with Galeterone, and the inhibitory activity ratio Galeterone of embodiment 2 and 3 is more preferable, moreover, the inhibitory activity of deuterated metabolin (embodiment 4,5,6) is also more preferable than not deuterated metabolin.In addition, it is also stronger to the inhibiting effect of PSA protein secretion, therefore the compounds of this invention ratio Galeterone is more suitable for for treating, preventing or eliminating various illnesss relevant to CYP17 enzyme and androgen receptor, such as prostate cancer.

(3) Pharmacokinetic Evaluation in rat.

8 male Sprague-Dawley rats, 7-8 week old, weight about 210g, it is divided into 2 groups, every group 4, single oral gives (a) control group of 5mg/kg dosage: 3 β -17- (1H- benzo [d] imidazoles -1- base) androstane -5,16- dien-3-ols；(b) test group: embodiment 1-3 compares its pharmacokinetic difference.

Rat is raised using standard feed, gives water.Test is fasted for first 16 hours.Drug is dissolved with PEG400 and dimethyl sulfoxide.Eye socket blood sampling, the time point of blood sampling are 0.083 hour, 0.25 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours after administration.

Rat sucks of short duration anesthesia after ether, and eye socket acquires 300 μ L sample of blood in test tube.There are 30 μ L1% heparin salting liquids in test tube.Before use, test tube is stayed overnight in 60 DEG C of drying.After being completed with the latter time point blood specimen collection, put to death after rat etherization.

It after blood specimen collection, leniently overturns test tube at least 5 times, is placed on ice after guaranteeing mixing sufficiently immediately.Blood sample is centrifuged 5 minutes in 4 DEG C of 5000rpm, and blood plasma is separated with red blood cell.100 μ L blood plasma are sucked out into clean plastic centrifuge tube with pipettor, show title and the time point of compound.Blood plasma is stored in -80 DEG C before being analyzed.With the concentration of the compounds of this invention in LC-MS/MS measurement blood plasma.Pharmacokinetic parameter is based on every animal blood concentration in different time points into calculating.

The experimental results showed that the compounds of this invention has better pharmacokinetics in animal body, thus has better pharmacodynamics and therapeutic effect relative to control compound.

(4) metabolic stability is evaluated.

Microsomal assay: people's hepatomicrosome: 0.5mg/mL, Xenotech；Rat liver microsomes: 0.5mg/mL, Xenotech；Coenzyme (NADPH/NADH): 1mM, Sigma Life Science；Magnesium chloride: 5mM, 100mM phosphate buffer (pH 7.4).

The preparation of stock solution: precision weighs the powder of a certain amount of COMPOUNDS EXAMPLE, and is dissolved to 5mM respectively with DMSO.

Phosphate buffer (100mM, pH7.4 preparation): the 0.5M dipotassium hydrogen phosphate solution of the 0.5M potassium dihydrogen phosphate 150mL and 700mL that prepare in advance is taken to mix, mixed liquor pH value is adjusted to 7.4 with 0.5M dipotassium hydrogen phosphate solution again, 5 times are diluted with ultrapure water using preceding, magnesium chloride is added, phosphate buffer (100mM) is obtained, wherein potassium phosphate containing 100mM, 3.3mM magnesium chloride, pH 7.4.

Prepare NADPH regenerative system solution (containing 6.5mM NADP, 16.5mM G-6-P, 3U/mL G-6-P D, 3.3mM magnesium chloride), using it is preposition in it is wet on ice.

Prepare terminate liquid: the acetonitrile solution containing 50ng/mL Propranolol Hydrochloride and 200ng/mL orinase (internal standard).It takes 25057.5 μ L phosphate buffers (pH7.4) into 50mL centrifuge tube, is separately added into 812.5 μ L people's hepatomicrosomes, mix, obtain the hepatomicrosome dilution that protein concentration is 0.625mg/mL.It takes 25057.5 μ L phosphate buffers (pH 7.4) into 50mL centrifuge tube, is separately added into 812.5 μ L SD rat liver microsomes, mix, obtain the hepatomicrosome dilution that protein concentration is 0.625mg/mL.

The incubation of sample: being diluted to 0.25mM for the stock solution of respective compound with the aqueous solution containing 70% acetonitrile respectively, spare as working solution.It takes people's hepatomicrosome of 398 μ L or rat liver microsomes dilution that 96 holes are added respectively to be incubated in plate (N=2), is separately added into the working solution of 2 μ L 0.25mM, mixes.

The measurement of metabolic stability: the terminate liquid of 300 μ L pre-cooling is added in every hole of 96 hole deep-well plates, is placed on ice, as termination plate.96 holes are incubated for plate and NADPH regenerative system is placed in 37 DEG C of water baths, 5min is incubated in 100 revs/min of concussions in advance.80 μ L Incubating Solutions addition termination plate is taken out from the every hole of plate is incubated for, mixes, 20 μ L NADPH regenerative system solution is supplemented, as 0min sample.Again to the NADPH regenerative system solution for being incubated for 80 μ L of the every hole addition of plate, starting reaction starts timing.The reaction of respective compound is dense Degree is 1 μM, protein concentration 0.5mg/mL.When reacting 10,30,90min, 100 μ L reaction solutions are respectively taken, are added in termination plate, vortex 3min terminates reaction.Termination plate is centrifuged 10min under the conditions of 5000 × g, 4 DEG C.It takes 100 μ L supernatants to being previously added in 96 orifice plates of 100 μ L distilled water, mixes, sample analysis is carried out using LC-MS/MS.

Data analysis: by LC-MS/MS system detection respective compound and interior target peak area, compound and internal standard peak area ratio are calculated.Slope is measured by the natural logrithm of the percentage of compound surplus and time mapping, and calculates t according to the following formula_1/2And CLint, wherein V/M is equal to 1/ protein concentration.

The compound of embodiment is analyzed according to above-mentioned steps, the results are shown in Table 2.

The experimental result of the metabolic stability of the substituted steroid compound of 2 Examples 1 to 6 of table

As shown in table 2, the compounds of this invention Increased Plasma Half-life, clearance rate reduce, and illustrate that the compounds of this invention can significantly improve metabolic stability.

The above content is a further detailed description of the present invention in conjunction with specific preferred embodiments, and it cannot be said that specific implementation of the invention is only limited to these instructions.For those of ordinary skill in the art to which the present invention belongs, without departing from the inventive concept of the premise, a number of simple deductions or replacements can also be made, all shall be regarded as belonging to protection scope of the present invention.

Claims

A kind of substituted steroid compound, it is characterised in that: the steroid compound as shown in formula (I):

In formula:

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹、R²²、R²³It is independently selected from the group being made of " hydrogen (H), deuterium (D) "；

X¹、X²It is independently selected from by " hydrogen (H), deuterium (D), methyl, CH₂D、CHD₂、CD₃、CH₂CH₃、CHDCH₃、CHDCH₂D、CHDCHD₂、CHDCD₃、CD₂CH₃、CD₂CH₂D、CD₂CHD₂、CD₂CD₃" composition group；

Y is selected from " hydrogen (H), deuterium (D), hydroxyl, acetyl group, one or many deuterated acetyl group "；

And its physiologically acceptable salt, prodrug, metabolin, solvate, tautomer and stereoisomer, the mixture formed including these compounds with all proportions；

Additional conditions are that the compound does not include non-deuterated compound.
Compound as described in claim 1, which is characterized in that R¹、R²、R³、R⁴、R⁵From independently being deuterium or hydrogen.
Compound as described in claim 1, which is characterized in that Y is selected from hydrogen, deuterium, hydroxyl, one or many deuterated acetyl group.
Compound as described in claim 1, which is characterized in that X¹、X²For methyl deuterated three times.
Compound as described in claim 1, which is characterized in that selected from the substituted steroid compound or its pharmaceutically acceptable salt in the following group, but be not limited to following compound:
A kind of pharmaceutical composition, it is characterized by: it contains pharmaceutically acceptable carrier and the steroidal compounds replaced as claimed in any one of claims 1 to 5, wherein or or mixtures thereof its crystal form, pharmaceutically acceptable salt, hydrate or solvate, stereoisomer, prodrug, metabolin, isotopic variations.
Pharmaceutical composition according to claim 6, it is characterized by: it also includes other treatment drug, the therapeutic agent is the drug of cancer, cell proliferation disorders, inflammation, infection, immunity disease, organ transplant, viral disease, cardiovascular disease or metabolic disease.
A kind of preparation method of pharmaceutical composition as claimed in claims 6 or 7, it is characterized by: by pharmaceutically acceptable carrier and the steroid compound that as claimed in any one of claims 1 to 5, wherein replaces, or its crystal form, pharmaceutically acceptable salt, prodrug, metabolin, stereoisomer, isotopic variations hydrate or solvate are mixed, and pharmaceutical composition is obtained.
A kind of purposes of the steroid compound replaced as claimed in any one of claims 1 to 5, wherein, it is characterised in that: can be used for treating, prevent or eliminate various CYP17 enzymes and androgen receptor (AR) associated disease (such as prostate cancer)；Pharmaceutical composition comprising these compounds is used to treat in different therapy fields such as cancer, prevents disease or obstacle or slow down the disease or obstacle process.
A method of disease relevant to CYP17 enzyme and androgen receptor (AR) is treated and/or prevented in subject, the method includes the pharmaceutical compositions to any one of snibject formula as claimed in any one of claims 1 to 5, wherein (I) compound or its polymorphic, pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic variations, hydrate or solvated compounds or claim 6 or 7.
Formula (I) compound or its polymorphic, pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic variations, hydrate or solvated compounds described in any one according to claim 1~5, or the pharmaceutical composition of any one of claim 6 or 7, it is used to treat and/or prevent disease relevant to CYP17 enzyme and androgen receptor (AR).