WO2008122198A1 - Régulateurs d'accepteurs androgènes non stéroïdes et leur utilisation médicale - Google Patents

Régulateurs d'accepteurs androgènes non stéroïdes et leur utilisation médicale Download PDF

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WO2008122198A1
WO2008122198A1 PCT/CN2008/000649 CN2008000649W WO2008122198A1 WO 2008122198 A1 WO2008122198 A1 WO 2008122198A1 CN 2008000649 W CN2008000649 W CN 2008000649W WO 2008122198 A1 WO2008122198 A1 WO 2008122198A1
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androgen
acid
pharmaceutically acceptable
androgen receptor
acceptable salt
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PCT/CN2008/000649
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English (en)
Chinese (zh)
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Mingwei Wang
Guohai Wu
Caihong Zhou
Qunyi Li
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Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
The National Center For Drug Screening
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Publication of WO2008122198A1 publication Critical patent/WO2008122198A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
    • C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens

Definitions

  • the present invention relates to the use of a class of non-androgen receptor modulators and pharmaceutical compositions thereof for the prevention and/or treatment of symptoms or diseases caused by androgen and androgen receptor dysfunction, including but not limited to middle-aged men Androgen partial deficiency syndrome, osteoporosis, muscle consumption (Sarcopenia female sexual insufficiency, anorexia, female hirsutism, severe androgen-dependent alopecia, acne, dysentery, benign prostatic hyperplasia, prostate cancer, breast cancer, Alzheimer's disease (AD) and Parkinson's disease (PD).
  • middle-aged men Androgen partial deficiency syndrome including but not limited to middle-aged men Androgen partial deficiency syndrome, osteoporosis, muscle consumption (Sarcopenia female sexual insufficiency, anorexia, female hirsutism, severe androgen-dependent alopecia, acne, dysentery, benign prostatic hyperplasia, prostate cancer, breast cancer, Alzheimer's
  • Androgen is an important steroidal sex hormone in the human body. It promotes cell differentiation and tissue growth by binding to the Androgen Receptor (AR) and participates in many key physiological functions such as male fetal reproductive organs (such as the prostate). , the formation of sputum, epididymis, etc.), the development and maintenance of secondary sexual characteristics, and sperm production.
  • a certain proportion of androgens such as Testosterone (T), Dihydrotestosterone (DHT), and Adrenal androsterone, are present in both men and women. In women, androsterone can be converted to estrogen in most target organs, but plays a normal physiological function in some tissues such as the brain. In the prostate and skin, androgen is converted to DHT by 5 ⁇ -reductase, and DHT has a 3-5-fold higher affinity for AR than quinone.
  • T Testosterone
  • DHT Dihydrotestosterone
  • Adrenal androsterone Adrenal androsterone
  • AR is a member of the nuclear receptor superfamily, a ligand-activated transcription factor that is widely distributed in proliferating and non-proliferating tissues, including prostate and sperm, male and female genitalia, testes, ovaries, skin, edulis, sweat glands, Cartilage, myocardium, bone and smooth muscle, adrenal cortex, liver, pineal gland and multiple cerebral cortical and subcortical regions, including spinal motor neurons (Negro-Vilar, J Clinical Endocrinology and Metabolism, 1999, 84: 3459-3462 ).
  • the AR protein has three domains: N-terminal structure (NTD), DNA-binding i or (DNA binding domain, DBD) binds to a ligand or (Ligand binding domain, LBD X He B, Kemppainen JA, 1999: J. Biol. Chem. 274: 37219-25). After the androgen and AR LBD form a complex, they bind to the Androgen response element (ARE) located in the promoter region of the target gene to activate or inhibit the expression of the purine gene, thereby regulating the physiological function of the target tissue. . Many AR-related diseases, either due to abnormal hormone levels or due to receptor dysfunction, disrupt normal interaction balance.
  • AR is an important target in the treatment of various diseases and symptoms associated with androgen action.
  • AR modulators can be used to prevent/treat diseases associated with age and androgen metabolism, such as androgen deficiency in older men, androgen deficiency in women, osteoporosis, muscle loss, female sexual insufficiency , anorexia, hirsutism in women, severe androgen-dependent alopecia, acne, and several morbid diseases.
  • AR modulators can be used to treat benign prostatic hyperplasia, hormone-dependent prostate cancer, and breast cancer; for neurological diseases, AR modulators can be used to treat depression, Alzheimer's disease, and Parkinson's syndrome (Segal) S., Naraynan R. and Dalton J. Expert Opin. Investig. Drugs 2006, 15: 377-387).
  • Steroidal androgens include, in addition to naturally occurring in the body, esters of androstenone such as cyclopentanoate, propionate, phenylpropionate, cyclopentylpropionate, heptanoate and decanoate. ), and other synthetic androgens (such as 7-methylnortestosterone and its acetate).
  • Antiandrogen is represented by Cyproterone acetate (CPA).
  • Non-steroidal AR modulators include Flutamide, Nilutamide, and Bicalutamide (Casodex), all of which are receptor antagonists.
  • non-steroidal AR agonists have also been reported in the literature and patents, but they have not yet entered clinical application. Both the steroidal and non-steroidal AR modulators have certain side effects, including causing metabolic disorders of the androgen and causing male breast development and liver toxicity. Patients with benign prostatic hyperplasia/prostate cancer who have long-term use of flutamide or bicalutamide may have side effects such as gastrointestinal discomfort, nausea, vomiting, insomnia, fatigue, headache, anxiety, blurred vision, and loss of libido. After the androgen drug, there will be “anti-male” “Antiandrogen withdrawal syndrome” (AWS), which shows that the PSA level that was originally inhibited after a period of administration has risen rapidly and the tumor volume has increased.
  • AWS Antiandrogen withdrawal syndrome
  • the present inventors disclose a class of non-steroidal androgen receptor modulators, methods for their preparation, pharmaceutical compositions and uses in the patent application CN200510026252.2. Although the use of such compounds as androgen receptor modulators is disclosed in the use, only the use of the compounds as androgen receptor antagonists is disclosed, and no use is made for their use as androgen receptor agonists. set forth.
  • the present invention prepares and optimizes a novel class of non-body small molecule compounds through chemical synthesis and structure-activity relationship studies.
  • the androgen receptor competition experiments showed that these compounds have an affinity for the receptor of less than 10 ⁇ , which is equivalent to DHT; luciferase 4 gene co-transfection experiments and prostate cancer cell line LNCaP proliferation experiments show that they have AR Partial agonism and antagonistic activity represent the potential for further development as a novel androgen receptor modulator.
  • non-steroidal androgen receptor modulator compound having the structure of the following formula I or a pharmaceutically acceptable salt thereof.
  • a further object of the present invention is to provide a pharmaceutical composition comprising a compound of the formula I or a pharmaceutically acceptable salt thereof.
  • a further object of the present invention is to provide a compound of the formula I or a pharmaceutically acceptable salt thereof as a non-steroidal androgen receptor modulator for the prevention or/and treatment of androgen and androgen receptor dysfunction The cause of the symptoms or diseases caused.
  • the compound of the present invention having a structure of the formula I or a pharmaceutically acceptable salt thereof is used as a non-steroidal androgen receptor agonist for the preparation of a prophylactic or/and therapeutic symptom caused by androgen and androgen receptor dysfunction or Use in disease.
  • the compound of the present invention having a structure of the formula I or a pharmaceutically acceptable salt thereof is used as a non-steroidal androgen receptor antagonist in the preparation of a prophylactic or/and therapeutic agent for symptoms caused by androgen and androgen receptor dysfunction or Use in disease.
  • the non-androgen receptor modulator or a pharmaceutically acceptable salt thereof provided by the present invention has the structure of the following formula I:
  • the acid is a mineral acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.; an organic acid such as formic acid, acetic acid, propionic acid, benzoic acid, horse Acid, fumaric acid, succinic acid, tartaric acid, citric acid, etc.; alkylsulfonic acid, such as methanesulfonic acid, ethylsulfonic acid, etc.; arylsulfonic acid, such as benzenesulfonic acid, p-toluenesulfonic acid, etc. use.
  • the acid is a mineral acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.
  • an organic acid such as formic acid, acetic acid, propionic acid, benzoic acid, horse Acid, fumaric acid, succinic acid, tartaric acid, citric acid, etc.
  • compositions provided herein comprise a therapeutically effective amount of one or more compounds of the formula I, or a pharmaceutically acceptable salt thereof, which may further comprise one or more pharmaceutically acceptable carriers Or an excipient.
  • a desirable ratio of the pharmaceutical composition provided by the present invention is that the compound of the formula I or a pharmaceutically acceptable salt thereof has an active ingredient in an amount of from 50% to 99.5% by weight based on the total weight ratio, and the remainder is less than 50% by weight based on the total weight.
  • a further object of the present invention is to provide prevention by administering an androgen receptor modulator or a pharmaceutically acceptable salt thereof (including a pharmaceutical composition thereof) as described herein, as an androgen receptor agonist and/or an antagonist.
  • And/or methods for treating various symptoms or diseases caused by androgen and androgen receptor dysfunction including but not limited to osteoporosis, muscle wasting, female sexual insufficiency, anorexia, female hirsutism, severe androgen Dependent hair loss, acne, seborrhea, dysentery (including but not limited to AIDS), benign prostatic hyperplasia, prostate cancer, androgenetic alopecia, benign or malignant tumors that express androgen receptors (eg, in the breast, brain, Cancer of tissues such as skin, ovary, bladder, lymph, liver, kidney and pancreas), Endometriosis, ovarian syndrome, Alzheimer's disease, Parkinson's disease, androgen-dependent/age-related diseases (eg, androgen partial deficiency syndrome in middle-aged men, male or female) Dysfunction and muscle atrophy in ambulatory patients, etc.). It is particularly preferably used for the treatment/prevention of androgen-dependent tumors, particularly prostate cancer, which reduces the
  • Figure 1 is a competitive binding activity test of a compound with DHT for AR.
  • Compound MWW6003 and MWW6015 rather, IC 5 and DHT AR affinity for both. Values were 2.23 ⁇ and 3.48 ⁇ ; compound MWW6009 and MWW6040 relatively weak affinity for AR, IC 50 values were 21.60 nM and 14.40 ⁇ , under the same conditions DHT IC 50 of 7.75 ⁇ .
  • Figure 2 is a cytotoxicity test of compounds in HeLa cells.
  • Compounds MWW6003 and MWW6015 were incubated with HeLa cells for three days and their effects on cell growth were determined by MTT assay, both showing only low cytotoxicity, with IC 5 of compound MWW6003.
  • the value is 2.8 ⁇ and the IC 50 of the MWW6015 is between 10 and 40 ⁇ .
  • Figure 3 is a pharmacological activity test of a compound in a CV-1 cell reporter transfection experiment.
  • Dihydrotestosterone (DHT) induces the expression of luciferase in cells to increase chemiluminescence readings, and the antagonism of compounds on androgen receptors appears to inhibit DHT-induced chemiluminescence.
  • MWW6003 and MWW6015 showed AR agonistic activity in agonistic mode, with potency of 122.7% and 107.0%, respectively, and EC 50 of 70.8 ⁇ and 122.1 nM, respectively;
  • Compound MWW6009 showed partial agonistic activity, EC 50 was 1206 ⁇ , and the potency was DHT.
  • FIG. 4 is a pharmacological activity test of the compound in the MDA-MB-453 cell reporter transfection experiment.
  • MWW6003, MWW6009 and MWW6015 show partial AR agonistic activity in the agonistic mode, The potency was 19.5%, 9.2%, and 20.4%, respectively, and EC 5 o was 239.3 ⁇ , 561.7 ⁇ , and 102.1 ⁇ , respectively.
  • the EC 50 of DHT was 0.6 ⁇ ; in the antagonistic mode, the compounds MWW6003 and MWW6015 showed A certain AR antagonistic activity, IC 5 o was 812.6 ⁇ and 84.8 ⁇ , respectively, the inhibition rates were 99.1% and 23.9%, respectively, while the IC 50 of Casodex was 400.4 ⁇ under the same conditions.
  • Figure 5 is a pharmacological activity test of the compound in the LNCaP cell proliferation assay.
  • LNCaP is a hormone-dependent prostate cancer cell, and both DHT and AR agonists induce proliferation.
  • AR antagonists can inhibit DHT-induced cell proliferation. The results showed that the compounds MWW6003 and MWW6015 showed some activity trends in both the agonistic and antagonistic modes.
  • modulator refers to a class of compounds that enhance (eg, agonists, have agonistic activity) or inhibit (eg, antagonists, have antagonistic activity) the biological activity or function of a prion protein (including enzymes, receptors, etc.), Moreover, its enhancement and inhibition only temporarily act on the occurrence of a specific event in a specific cell or tissue, such as signal transduction, transcriptional activation and the like.
  • mistunasemiconductor Deficiency of the aging male refers to the progressive reduction of male androgen production after middle age.
  • Clinical manifestations include fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, alopecia, obesity , senile muscle atrophy, osteopenia, benign prostatic hyperplasia, anemia, mood and cognitive changes, and prostate cancer.
  • the occurrence of PADAM is related to the androgen environment and can be corrected by controlling the androgen environment.
  • Osteoporosis is a systemic skeletal disorder characterized by low bone density and degeneration of bone tissue, which increases bone fragility and susceptibility to fracture. Femoral fractures are the most serious outcome of osteoporosis, with 5-20% of patients dying within one year and more than 50% of survivors losing their ability to live. Older people are at greatest risk for osteoporosis, and their incidence increases significantly with ageing. In addition, women are more likely to develop osteoporosis than men. The physiological concentrations of androgen and estrogen play an important role in maintaining bone homeostasis throughout the life cycle.
  • prostatic hyperplasia refers to a type of benign adenomatous hyperplasia of the prostate surrounding the urethra that causes varying degrees of bladder outflow obstructive disease or symptoms, also known as “benign prostatic hypertrophy.”
  • Prostatic hyperplasia is one of the most common diseases in urology and has become a "stealth killer” that threatens men's health.
  • Clinical statistics show that men have a prevalence of benign prostatic hyperplasia of about 50% between the ages of 40 and 79, and up to 80% after age 80. As the pace of life continues to accelerate, the number of patients with benign prostatic hyperplasia is increasing, and it is younger.
  • Benign prostatic hyperplasia can also cause a variety of potential complications, such as acute urinary retention, urinary tract infection, fleshy urine, bladder diverticulum, stones, hydronephrosis and renal failure. Studies have shown that dihydrotestosterone is the most important cause of benign prostatic hyperplasia in patients, and anti-androgen therapy can help to improve its symptoms.
  • prostate cancer refers to a type of malignant tumor common to the male reproductive system, which is predominantly adenocarcinoma. Prostate cancer is a serious male senile disease with very high morbidity and mortality rates in Europe and America. High, accounting for the first place in male malignancies (Landis SH, Murray T, 1998, CA Cancer J. Clin. 48: 6-29). The incidence of prostate cancer in China is lower than in Europe and the United States, but in recent years, with the elderly The acceleration of the degree of regulation, the changes in the traditional diet structure, and the improvement of the diagnostic level of such diseases, the incidence rate has increased significantly. In addition to early prostate cancer can be surgically removed, anti-androgen therapy is the clinical choice.
  • hirsutism refers to a hirsutous symptom in women caused by an increase in androgen secretion, that is, a long, thick, black hair, or hair, that grows in areas that should not have long hair. It is male-type, with thick and dark eyebrows and pubic hair developing to the abdomen and even the umbilicus.
  • severe androgen-dependent alopecia refers to a type of severe seborrheic alopecia, also known as male pattern alopecia.
  • acne refers to the chronic inflammation of a type of edema sebaceous gland, which occurs in the face, chest and back, and is characterized by acne, papules, pustules, nodules, carbuncle, etc., also known as youth acne.
  • Alzheimer's disease is a group of primary degenerative brain degeneration diseases whose etiology is unknown. The pathological changes are mainly diffuse atrophy of the cortex, widening of the sulcus, enlargement of the ventricles, reduction of neurons, and visible Lesions of senile plaques, neurofibrillary tangles, granular vacuoles, and choline acetylase and acetylcholine were significantly reduced. Alzheimer's disease is more common in the elderly, latent onset, slow and irreversible progress (two years or longer), mainly based on intelligent damage.
  • Parkinson's disease is a common central nervous system degenerative disease in middle-aged and elderly people, mainly characterized by slow patient movement, tremors in the hands, feet or other parts of the body, loss of softness in the body, and muscle stiffness. Parkinson's disease is second only to tumors and cardiovascular and cerebrovascular diseases, and is called the “third killer” and "chronic cancer”. Okun et al confirmed that androgen supplementation helps improve Symptoms of the disease ( Okun MS, Walter BL, Mcdonald WM, et al. 2002, Arch. Neurol. 59: 1750-1753).
  • an "effective amount" of a compound for treating a particular condition refers to an amount sufficient to ameliorate or to some extent alleviate the symptoms associated with the disease.
  • This dose can be administered in a single dose or in a therapeutic regimen. This dose cures the disease, but is typically administered to improve the condition. Repeated administration to improve symptoms may be desirable.
  • pharmaceutically acceptable salts, esters or other derivatives include any salt, ester or derivative which is readily prepared by those skilled in the art by known methods.
  • the compounds thus derived and produced can be administered to animals and humans without toxic effects.
  • the compound is either pharmaceutically active or a prodrug.
  • treatment means that the disease and symptoms are improved in any way, or other beneficial changes. Treatment also includes the use of the compounds of the invention in medicine.
  • administration of a particular pharmaceutical composition to "improve" the symptoms of a particular disease means any reduction, whether permanent, temporary, prolonged, transient, can be attributed to or associated with the pharmaceutical composition. Relevant application.
  • substantially pure means sufficient homogeny to detect impurities by standard analytical methods used by those skilled in the art for evaluating purity, such as thin layer chromatography (TLC), gel electrophoresis. And high performance liquid chromatography (HPLC). Or sufficiently pure also means that even further purification does not alter the physicochemical properties detectable by the substance, such as enzymatic activity and biological activity.
  • Methods for producing substantially chemically pure compounds for purification are well known to those skilled in the art. However, substantially chemically pure compounds can be stereoisomers or mixtures of isomers. In this case, further purification may increase the specific activity of the compound.
  • prodrug refers to a compound administered in vivo that can be metabolized or converted to a biologically, pharmaceutically or therapeutically active form.
  • the pharmaceutically active compound will be modified to reproduce the active compound by metabolic processes.
  • Prodrugs can be designed to alter their metabolic stability, or transport properties of precursors, to mask their side effects or toxicity, improve The taste of the drug, or other characteristics.
  • substantially are the same or are homogenous or similar, and the understanding of the relevant art can vary in the context, and is generally at least 70%, preferably at least 80%, more preferably at least 90%, in accordance with the understanding of the relevant art. Optimally at least 95% identical.
  • composition refers to any mixture. It can be a solution, suspension, liquid, powder, ointment, aqueous, non-aqueous or any combination thereof.
  • subject as used herein includes humans and animals, for example, dogs, cats, cows, pigs, rodents, etc., preferably humans.
  • An experienced practitioner should understand that the subject is suitable and willing to suffer from orrogen and/or androgen receptor dysfunction or associated with androgen partial deficiency syndrome, osteoporosis, muscle wasting, anorexia, Treatment and prevention of diseases and conditions such as female hirsutism, severe androgen-dependent alopecia, acne, dysentery, benign prostatic hyperplasia, prostate cancer, breast cancer, Alzheimer's disease and Parkinson's disease.
  • the compounds of the invention are formulated for any suitable route of administration, such as intraluminal, subcutaneous, intravenous, intramuscular, intradermal injection. Oral or topical.
  • the method can be administered by injection, in a single dose, in an ampoule, or in a multi-dose container with an additional buffer.
  • the formulations may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles.
  • the formulations may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient can be in powder form and suitable before use.
  • the carrier, sterile non-pyrogenic water or other solvent constitutes a dosage form.
  • the topical medicament of the present invention may be a foam, a gel, an ointment, an ointment, a transdermal patch or a paste.
  • compositions and methods for administration which can be used in the present invention include, but are not limited to, those disclosed in U.S. Patent Nos. 5,736,154, 6,197,801 B1, 5,741,511, 5,886,039, 5,941,868, 6,258,374, and 5,686,102.
  • the size of the dose to be treated or prevented will vary depending on the severity of the condition and the route of administration.
  • the frequency of dosing and medication will vary with age, weight, health status, and individual patient response.
  • Dosage forms include tablets, troches, soy gums, dispersing agents, suspending agents, solutions, capsules, films and the like.
  • the compound of the present invention may be in accordance with general pharmaceutical mixing techniques with pharmaceutical carriers or excipients such as ⁇ -cyclodextrin and 2-hydroxy-propyl- ⁇ -cyclodextrin. Finely mixed.
  • a special carrier a local or parenteral route, may be employed.
  • parenteral dosage forms such as compositions for intravenous injection or infusion
  • similar pharmaceutical vehicles can be employed, water, glycols, oils, buffers, sugars, preservatives, liposomes, etc., which are well known to those skilled in the art. .
  • parenteral compositions include, but are not limited to, 5% w/v dextrose, physiological saline or other solutions.
  • the total dose of the compound of the present invention, alone or in combination with other preparations, can be administered in vials of intravenous injection, in a volume of from about 1 ml to about 2000 ml. The amount of diluent will vary depending on the total dose administered.
  • the invention also provides a kit for achieving a therapeutic regimen.
  • the kit comprises an effective amount of a compound of the invention, in a pharmaceutically acceptable form, alone or in combination with other agents, in one or more containers.
  • a preferred pharmaceutical form is in combination with sterile saline, dextrose solution, buffered solution, or other pharmaceutically acceptable sterile liquid.
  • the composition can be lyophilized or dried; in this case, the kit
  • a pharmaceutically acceptable solution preferably a sterile solution, is contained in a container to reconstitute the complex to form a solution for injection purposes.
  • Typical pharmaceutically acceptable solutions are saline solutions and dextrose solutions.
  • the kit of the present invention further comprises a needle or syringe and/or a packaged alcohol pad for injection of the composition, preferably in sterile form. Instructions for use by a doctor or patient may optionally be included.
  • the obtained solid was suspended in 150 ml of 95% ethanol, stirred at room temperature for 2 hours, neutralized with saturated NaHC0 3 to basicity, stirring was continued for 1 hour, suction filtration, and the filter cake was washed with a small amount of anhydrous ethanol, and the crude product was mixed with ethanol/water.
  • the solvent (1:1) was recrystallized to obtain 30.66 g of needle crystals, yield 72.1%.
  • the resulting solid was suspended in 10 ml 95% ethanol was stirred at room temperature for 30 minutes, 10% NaHC0 3 aqueous solution to alkaline and stirring was continued for 30 minutes, filtered off with suction, the filter cake washed with a small amount of ethanol, the crude product from ethanol / The water mixed solvent (1:1) was recrystallized to obtain 0.567 g of needle crystals, yield 65.7%.
  • Plasmids and cell lines were constructed by National New Drug Screening Center; human cervical cancer epithelial cell line HeLa, monkey kidney epithelial cell CV-1, human breast cancer cell line MDA-MB -453 and human prostate cancer cell line LNCaP were purchased from ATCC, USA.
  • Fetal bovine serum Fetal bovine serum (FBS, GIBCO/BRL, USA); Activated carbon and dextran treatment of fetal bovine serum (CD-FBS, Hyclone, USA); DMEM and RPMI1640 medium (GIBCO/BRL, USA) IMEM medium (Bioresource, USA), Luciferase Assay Kit (Promega Corporation, USA); Fugene 6 (Roche Ltd., USA);
  • Diarsonone (Dehydrotestosterone, DHT, Amersham, UK); Scintillation fluid (SuperMixTM, PerkinElmer, USA); Androgen receptor protein is the expression product of this receptor gene in insect cells.
  • the gradient solution of DHT and the compound of the present invention shown in Figure 1 was prepared in DMSO, and the DHT and compound concentrations were 0, 0.128, 0.64, 3.2, 16, 80, 400, 2000 ⁇ , respectively, and 5 ⁇ each gradient DHT or The test compound solution is placed in each well of the tube.
  • the androgen receptor protein is added to a protease inhibitor such as 1 ⁇ aprotinin and Leupeptin.
  • HeLa cells were cultured in RPMI1640 medium containing 10% FBS and 2 mM L-glutamine, and were grown to 90% confluence, and then trypsinized and added to the 96-well plate at 4000/well, 37 Incubate overnight at °C.
  • the test compound was diluted to a certain concentration and added to the cells.
  • the concentrations of the compounds MWW6003 and MWW6015 were 0, 2.56, 12.8, 64.0, 320, 1600, 8000, 40,000 ⁇ , and the MTT solution (5 mg/mL) was added after 68 hours of culture. , 20 ⁇ 7 well, measured 560nm light absorption value, reference The wavelength is 690 nM.
  • the experimental results show that the compounds MWW6003 and MWW6015 have only low cytotoxicity to HeLa cells, IC 5 of MWW6003. With a value of 2.8 ⁇ , the MWW6015 has an IC 50 value between 10 and 40 ⁇ (see Figure 2).
  • CV-1 cells were cultured in DMEM medium containing 10% FBS and 2 mM L-glutamine. The day before transfection, the cells were replaced with DMEM medium containing 10% CD-FBS, and transfected with Fugene 6 reagent. The AR expression plasmid, the 4 reporter gene vector and Fugene 6 were uniformly added dropwise to the cells at a ratio of 1:10:30, and cultured at 37 ° C and 5% CO 2 for 6 hours. After the cells were digested, the cells were inserted into a 96-well culture plate at 8000/100 ⁇ M/well, and cultured in DMEM medium containing 10% CD-FBS at 37 ° C for 16 hours. Add the compound to be tested.
  • the DHT concentrations were 0, 0.01, 0.1, 1, 10, 100, and 1000 ⁇
  • the concentrations of the 4 conjugates MWW6003 and MWW6015 were 0, 2.6, 13, 64, 320, 1600, 8000 ⁇
  • the concentrations of the compounds MWW6009 and MWW6040 were 0, 3.2, 16, 80, 400, 2000, 10000 ⁇ .
  • the concentrations of Bicalutamide (Casodex) were 0, 0.01, 0.1, 1, and 10. 100, 1000, 10000 ⁇
  • the concentration of compound MWW6009 was 0, 3.2, 16, 80, 400, 2000, 10000 ⁇
  • 2 ⁇ DHT was added to the cells as an agonist.
  • the luciferase assay kit was used to detect the enzyme activity to evaluate the pharmacological activity of the compound on the androgen receptor.
  • the agonistic activities of the compounds MWW6003 and MWW6015 were stronger, with EC 5 o of 70.8 ⁇ and 122.1 ⁇ , respectively, and the potency was 122.7% and 107.0%, respectively, which was equivalent to DHT, while the agonistic activity of compound MWW6009 was relatively weak.
  • EC 5 o was 1206 nM, performance is 26.2%.
  • MWW6009 also showed a certain antagonistic activity with an IC 50 of 80.43 ⁇ , while the IC 50 of Casodex was 100.1 ⁇ under the same conditions (see Figure 3).
  • MDA-MB-453 cells were cultured in IMEM medium containing 10% FBS and 2 mM L-glutamine. The day before transfection, the cells were replaced with IMEM medium containing 5% CD-FBS, and Fugene 6 reagent was used for transfection. Mix the reporter gene carrier and Fugene 6 in a 1:3 ratio and add them dropwise. The cells were cultured for 6 hours at 37 ° C and 5% CO 2 . After the cells were digested, the cells were inserted into a 96-well culture plate at 20,000 cells/100 ⁇ M/well, and cultured in IMEM medium containing 5% CD-FBS at 37 ° C for 2 hours. Add the compound to be tested.
  • the concentrations of DHT, MWW6003 and MWW6015 are 0, 0.01, 0.1, 1, 10, 100, 1000, 10000 ⁇ , and the concentrations of MWW6009 are 0, 3.2, 16, 80, 400, 2000, 10000 ⁇ .
  • the concentrations of Casodex and MWW6003 are 0, 0.01, 0.1, 1, 10, 100, 1000, 10000 ⁇ , and the concentrations of MWW6015 are 0, 3.2, 16, 80, 400, 2000, 10000 ⁇ , At the same time, 5 ⁇ DHT was used as an agonist in the cells.
  • luciferase assay kit was used to detect the enzyme activity to evaluate the pharmacological activity of the compound on the androgen receptor.
  • Compounds MWW6003, MWW6009 and MWW6015 showed partial AR agonistic activity in agonistic mode with potency of 19.5%, 9.2% and 20.4%, respectively, and EC 50 of 239.3 ⁇ , 561.7 ⁇ and 102.1 ⁇ , respectively, under the same conditions. 5 .
  • both compounds MWW6003 and MWW6015 showed certain AR antagonistic activities with IC 5 o of 812.6 nM and 84.8 ⁇ , respectively, and the inhibition rates were 99.1% and 23.9%, respectively, while Casodex under the same conditions.
  • the IC 50 is 400.4 nM (see Figure 4).
  • LNCaP cells were cultured in RPMI 1640 medium containing 10% FBS and 2 mM L-glutamine. One day before the experiment, the cells were replaced with RPMI1640 medium containing 5% CD-FBS, and were incubated until 90%. After trypsinization, the cells were added to a 96-well plate at 4000/90 ⁇ 7 well, and cultured at 37 ° C overnight. The test compound was diluted to a certain concentration and added to the cells at 10 ⁇ 7 well.
  • the concentration of DHT, MWW6003 and MWW6015 was 0, 0.01, 0.1, 1, 10, 100, 1000, 10000 ⁇ in the agonist mode; antagonistic pattern detection
  • the concentrations of Casodex and the compounds MWW6003 and MWW6015 were 0, 0.01, 0.1, 1, 10, 100, 1000, 10000 ⁇ , and 5 ⁇ DHT was added as an agonist to the cells.
  • the culture was carried out for 6 days at 37 ° C, and the dressing was changed once on the third day. Before the end of the culture, MTT solution (5 mg/mL) was added, 20 ⁇ 7 wells, and the absorbance at 560 nm was measured, and the reference wavelength was 690 nm.
  • the experimental data is shown in Figure 5.
  • Compounds MWW6003 and MWW6015 are both agonistic and antagonistic. Show a certain activity trend (see Figure 5).
  • Compounds MWW6003 and MWW6015 showed good binding activity in the androgen receptor competitive binding activity test, and their IC 5 o values were less than 10 nM, which was comparable to DHT; compounds MWW6009 and MWW6040 also showed certain AR binding activity. .
  • Compounds MWW6003 and MWW6015 showed better agonistic activity in CV-1 cells co-transfected with AR expression vector and luciferase reporter gene expression vector, and their potency was comparable to DHT; MWW6009 also showed weak AR activation And antagonistic activity.
  • Compounds MWW6003 and MWW6015 showed good androgen receptor agonistic/antagonistic activity in the MDA-MB-453 cell reporter assay; a certain agonistic/antagonistic activity trend was also demonstrated in the LNCaP proliferation assay.

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Abstract

L'invention concerne des régulateurs d'accepteurs androgènes non stéroïdes représentés par la formule (I) ou des sels pharmaceutiquement acceptable de ceux-ci, utilisés pour préparer des médicaments non stéroïdes pour la prophylaxie et/ou le traitement d'un déficit androgène partiel chez un homme vieillissant, de l'ostéoporose, de la sarcopénie, d'un dysfonctionnement sexuel féminin, de l'anorexie, de l'hirsutisme féminin, de l'alopécie androgène sévère, de l'acné, de la cachexie, de l'hyperplasie bénigne de la prostate, du cancer de la prostate, du cancer du sein, de la maladie d'Alzheimer, de la maladie de Parkinson et analogue. L'invention concerne également des compositions pharmaceutiques contenant les composés représentés par la formule (I) ou des sels pharmaceutiquement acceptables de celles-ci et l'utilisation destits composés ou sels pour préparer des médicaments pour traiter les troubles ou maladies précités.
PCT/CN2008/000649 2007-04-09 2008-03-31 Régulateurs d'accepteurs androgènes non stéroïdes et leur utilisation médicale WO2008122198A1 (fr)

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WO1998053826A1 (fr) * 1997-05-30 1998-12-03 The University Of Tennessee Research Corporation Composes agonistes non steroidiens et leur utilisation dans le cadre de therapies a base d'hormones males
WO2002016310A1 (fr) * 2000-08-24 2002-02-28 The University Of Tennessee Research Corporation Modulateurs selectifs du recepteur androgenique et procedes d'utilisation de ces derniers
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WO1998053826A1 (fr) * 1997-05-30 1998-12-03 The University Of Tennessee Research Corporation Composes agonistes non steroidiens et leur utilisation dans le cadre de therapies a base d'hormones males
WO2002016310A1 (fr) * 2000-08-24 2002-02-28 The University Of Tennessee Research Corporation Modulateurs selectifs du recepteur androgenique et procedes d'utilisation de ces derniers
CN1869002A (zh) * 2005-05-27 2006-11-29 中国科学院上海药物研究所 一类非甾体雄激素受体调节剂、其制备方法和用途

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YI L. ET AL.: "The Mannich reaction between aromatic ketones, aromatic aldehydes and aromatic amines", SYNTHESIS, no. 9, September 1991 (1991-09-01), pages 717 - 718, XP003004278 *

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