RU2724103C2

Selective androgen receptor destroying agents (sard) and methods of using thereof

Abstract

FIELD: pharmaceuticals. SUBSTANCE: invention relates to compounds—selective androgen receptor destructors (SARD), represented by structure of formulas I and VII. In formula, I T is OH; Z is CN; Y is CF3; R1 is CH3; R2 is hydrogen, C1-C12-alkyl; Q1, Q4 and Q5 are each independently selected from hydrogen, CN; Q2 and Q3 each represent hydrogen or phenyl substituted with halogen; where at least two Q1, Q2, Q3, Q4 and Q5 are not hydrogen; or Q2 and Q3 are bonded together to form unsubstituted C5-C8-carboxyclic ring. In formula VII, T denotes OH; Z is CN; Y is CF3; R1 is CH3 and Q1 is F, Cl, Br, I. Invention also refers to specific compounds of said formulas and a pharmaceutical composition containing them. (I) (VII). EFFECT: selective androgen receptor destructive ligands (SARD) and methods for use thereof are disclosed. 15 cl, 8 tbl, 12 ex, 12 dwg

RU2724103C2, drawing sheet 1 — Sheet 1 of 73

Term

9.6 yearsleft in the term

Expires 21 April 2036.

15 claims: 10 independent, 5 dependent

1
Соединение - селективный разрушитель андрогенных рецепторов (SARD), представленное структурой формулы I , I где T представляет собой OH;Z представляет собой CN;Y представляет собой CF 3 ;R 1 представляет собой CH 3 ;R 2 представляет собой водород, C 1 -C 12 -алкил;Q 1 , Q 4 и Q 5 каждый независимо выбран из водорода, CN;Q 2 и Q 3 каждый представляет собой водород или фенил, замещенный галогеном;где по меньшей мере два Q 1 , Q 2 , Q 3 , Q 4 и Q 5 не представляют собой водород;или Q 2 и Q 3 соединены вместе с образованием незамещенного C 5 -C 8 -карбоциклического кольца.
2
Соединение SARD по п. 1, представленное структурой формулы III , III где Z представляет собой CN;Y представляет собой CF 3 ;R 2 представляет собой водород, C 1 -C 12 -алкил;Q 1 выбран из водорода, CN;Q 2 и Q 3 каждый представляет собой водород или фенил, замещенный галогеном.
3
Соединение - селективный разрушитель андрогенных рецепторов (SARD), представленное структурой формулы VII , VII где T представляет собой OH;Z представляет собой CN;Y представляет собой CF 3 ;R 1 представляет собой CH 3 и Q 1 представляет собой F, Cl, Br, I.
4
Соединение SARD по любому из пп. 1, 2, где Q 1 представляет собой CN.
5
Соединение SARD по п. 3, где Q 1 представляет собой F.
6
Соединение SARD по п. 1 или 2, представленное структурой любого из следующих соединений:16 или 19
7
Соединение SARD, представленное любым одним из , 17 , 18 49 или 50
8
Фармацевтическая композиция, обладающая эффектом селективного разрушителя андрогенных рецепторов (SARD), содержащая фармацевтически эффективное количество соединения SARD по любому из пп. 1-7 и фармацевтически приемлемый носитель.
9
Соединение по любому из пп. 1-7 для применения в лечении, подавлении, уменьшении частоты возникновения заболевания, снижении тяжести или ингибировании прогрессирования рака предстательной железы (PCa) и его симптомов, или увеличении выживаемости субъекта мужского пола, страдающего раком предстательной железы.
10
Соединение по п. 9, где рак предстательной железы представляет собой прогрессирующий рак предстательной железы, кастрационно-резистентный рак предстательной железы (CRPC), метастатический CRPC (mCRPC), неметастатический CRPC (nmCRPC), высокорисковый nmCRPC или любую их комбинацию.
11
Соединение по любому из пп. 9 или 10, где указанный субъект дополнительно принимает терапию андрогенной депривации (ADT) или указанный субъект не прошел терапию андрогенной депривации (ADT).
12
Соединение по любому из пп. 9 или 10, где указанный рак устойчив к лечению антагонистом андрогенных рецепторов или ингибитором лиазы.
13
Соединение по любому из пп. 1-7 для применения в лечении, подавлении, уменьшении частоты возникновения заболевания, снижении тяжести или ингибировании прогрессирования болезни Кеннеди, акне, в уменьшении производства кожного сала, гирсутизма, алопеции, гиперандрогенных гормональных состояний у женщин, вирилизации, синдрома андрогенной нечувствительности, AR-экспрессирующего рака, амиотрофического бокового склероза (ALS) или фибромы матки у субъекта.
14
Соединение по п. 13, отличающееся тем, что указанное гиперандрогенное гормональное состояние у женщин представляет собой преждевременное половое созревание, раннее половое созревание, дисменорею, аменорею, синдром многоклеточной матки, эндометриоз, гистериомиому, аномальное маточное кровотечение, раннее менархе, фиброзно-кистозную болезнь молочной железы, фибромы матки, кисты яичников, синдром поликистозных яичников, преэклампсию, эклампсию беременности, преждевременные роды, предменструальный синдром и/или сухость влагалища.
15
Соединение по п. 13, отличающееся тем, что указанный AR-экспрессирующий рак представляет собой рак молочной железы, рак яичек, рак матки, рак эндометрия, рак яичников, урогенитальный рак, рак мозга, рак кожи, меланому, лимфому, рак печени, рак почки, остеосаркому, рак поджелудочной железы, рак эндометрия, рак легких, немелкоклеточный рак легкого (NSCLC), рак толстой кишки, перианальные аденомы, рак центральной нервной системы, рак мочевого пузыря или любую их комбинацию.

Independent claims15

703 paragraphs in 21 sections, as filed

Technical field

This invention relates to 3-aminopropanamide compounds - selective androgen receptor destroyers, pharmaceutical compositions and their use in the treatment of prostate cancer, advanced prostate cancer, castration-resistant prostate cancer, androgenetic alopecia or other hyperandrogenic skin diseases, Kennedy disease, amyotrophic lateral sclerosis (ALS), and uterine fibroids, as well as methods for lowering full length androgen receptor (AR-FL) levels, including pathogenic and / or resistant mutations, AR splicing (AR-SV), and pathogenic polyglutamine (polyQ) polymorphisms of AR in a subject.

State of the art

Prostate cancer (PCa) is one of the most commonly diagnosed types of cancer among men in the United States and is the second leading cause of cancer deaths with more than 200,000 new cases and more than 30,000 deaths per year in the United States. The RSa therapy market is growing at an annual rate of 15-20% globally.

Androgen deprivation therapy (ADT) is the standard treatment for progressive PCa. Patients with advanced prostate cancer undergo ADT either by luteinizing hormone releasing hormone (LHRH) agonists, LHRH antagonists, or bilateral orchiectomy. Despite the initial response to ADT, disease progression is inevitable, and cancer occurs as castration-resistant prostate cancer (CRPC). Up to 30% of patients with prostate cancer who undergo primary treatment with radiation or surgery develop a metastatic disease within 10 years after the initial therapy. Approximately 50,000 patients a year develop a metastatic disease called metastatic CRPC (mCRPC).

Patients with CRPC have an average lifespan of 12-18 months. Despite castration resistance, CRPC is still dependent on the axis of androgen receptor signaling (AR) for further growth. The main reason for the reappearance of CRPC is the re-activation of AR by alternative mechanisms, such as: 1) intracrine synthesis of androgens; 2) variants of AR splicing (AR-SV), in which there is no ligand binding domain (LBD); 3) AR-LBD mutations that can resist AR antagonists (i.e. mutants that are not sensitive to inhibition by AR antagonists, and in some cases AR antagonists act as AR agonists carrying these LBD mutations); and 4) amplification of the AR gene in the tumor.

A critical barrier to progress in CRPC treatment is that AR signaling inhibitors such as enzalutamide, flutamide, bicalutamide and an abirator acting through LBD cannot inhibit N-terminal domain (NTD) -dependent, constitutively active AR- ST Recent highly effective clinical trials with enzalutamide and abiraterone in patients with CRPC have shown that 0% of patients expressing AR-V7 (predominant AR-SV) responded to any of these treatments, showing the need for next-generation AR antagonists that target AR -SV. In addition, a significant number of patients with CRPC become immune to abiraterone or enzalutamide, emphasizing the need for the use of next-generation AR antagonists.

Current evidence suggests that CRPC growth is dependent on constitutively active ARs, including AR-SVs that lack LBD, such as AR-V7, and therefore cannot be inhibited by conventional antagonists. AR inhibition and degradation by binding to a domain other than ARLBD provide alternative strategies for managing CRPC.

Molecules that destroy AR prevent any inadvertent activation of AR through growth factors or signaling pathways, or mixed ligand-dependent activation of AR. In addition, molecules that inhibit the constitutive activation of AR-SV are extremely important to provide lasting benefits to patients with CRPC.

Only a few AR-destroying chemotypes are currently known, which include SARDAZD-3514, ARN-509, and ASC-J9. However, these molecules destroy AR indirectly at much higher concentrations than their binding coefficient, and they are not able to destroy AR-SV, which in recent years has become the main reason for the renewal of untreated CRPC.

The present invention describes new unique pharmacological AR antagonists that strongly (high potentiality and effectiveness) and selectively bind AR (better than known antagonists), antagonize AR and destroy full length AR (AR-FL) and AR-SV. Compounds of selective androgen receptor disruptors (SARDs) have double degradation and inhibitory functions of AR-SV and, therefore, differ from any available therapeutic therapy using CRPC. These new compounds of selective androgen receptor disrupters (SARDs) inhibit the growth of PCA cells and tumors that depend on AR-FL and AR-SV for proliferation.

SARDs have the potential to develop as new therapeutic agents for treating CRPC that are not treatable with any other antagonists. This unique destruction property of AR-SV has extremely important health consequences for prostate cancer. To date, only one molecule (EPI-001) has been reported to bind to AR-NTD and inhibit AR function and PCa cell growth, albeit with lower affinity, and has the inability to destroy the receptor. The SARDs of this invention also bind AR-NTD and inhibit NTD-driven (i.e., ligand-independent) AR activity.

A positive correlation between AR and PCa and the lack of a reliable AR antagonist underlines the need for molecules that inhibit AR function through new or alternative binding mechanisms and / or sites, and which can cause antagonistic effects in an altered cellular environment.

Traditional antiandrogens such as bicalutamide and flutamide have been approved for use in prostate cancer. Subsequent studies have demonstrated the usefulness of antiandrogens (e.g. flutamide, spironolactone, cyproterone acetate, finasteride and chlormadinone acetate) in androgen-dependent dermatological conditions such as androgenetic alopecia (male pattern baldness), juvenile acne, and excessive hair growth. Prepubertal castration prevents the formation of sebum and androgenic alopecia, but this can be reversed with testosterone, which indicates its androgenic dependence.

The AR gene has a polymorphism of glutamine repeats (polyQ) in exon 1, which, when reduced, can enhance the transactivation of AR (i.e. hyperandrogenism). It has been found that shortened polyQ morphisms are more likely to occur in people with alopecia, excessive hair growth and acne. Classical antiandrogens are undesirable for these purposes, because they are ineffective by skin dosage, and their long-term systemic use increases the risk of adverse sexual effects such as gynecomastia and impotence. In addition, similar to the CRPC described above, inhibition of ligand-dependent activity may not be sufficient since AR may be activated by various cellular factors other than endogenous testosterone (T) and dihydrotestosterone (DHT), such as growth factors, kinases, excess co-activator expression and / or mixed activity to other hormones (e.g., estrogens or glucocorticoids). Therefore, blocking the binding of T and DHT to AR with the classic antiandrogen may not be sufficient to achieve the desired efficacy.

The new concept is the local application of SARD to destroy AR localized in affected areas of the skin or other tissue (s) without any systemic antiandrogenism. For this, the use of SARD, which does not penetrate the skin or is rapidly metabolized, will be preferable.

Confirmation of this approach is the observation that it has been shown that healing of skin wounds is suppressed by androgens. Castration of mice accelerates the healing of skin wounds, reducing inflammation in the wounds. A negative correlation between androgen levels and skin healing and inflammation, in particular, explains yet another mechanism in which high levels of endogenous androgens exacerbate hyperandrogenic dermatological conditions, such as those described herein. In addition, it provides the rationale for treating wounds, such as diabetic ulcers or even injuries, or skin diseases with an inflammatory component, such as acne or psoriasis, with local SARDs.

Androgenic alopecia occurs in ~ 50% of Caucasian middle-aged men and up to 90% at the age of 80. Minoxidil (a local vasodilator) and finasteride (a systemic inhibitor of type 5 alpha-reductase type II) are approved by the FDA for alopecia, but require 4-12 months of treatment to get a therapeutic effect and only stop hair loss in most cases from mild to moderate regrowth hair for 30-60%. Since currently available treatments have slow and limited efficiencies that vary widely between people and produce unwanted sexual side effects, it is important to find a new approach to the treatment of androgenetic alopecia and other hyperandrogenic dermatological diseases.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Patients with ALS are characterized by prolonged repetitions of AR polyglutamines. Riluzole is an affordable drug for treating ALS, but it provides only short-term effects. There is an urgent need for medications that will prolong the survival of patients with ALS. It was shown that transgenic ALS animals survive longer with castration and a decrease in AR levels compared with the addition of castration + nandrolone (agonist). Castration reduces AR levels, which can be the reason for long-term survival.

Androgens promote uterine proliferation. Higher testosterone levels increase the risk of uterine fibroids. Treating uterine fibroids with SARD can help prevent or treat uterine fibroids.

In this document, we describe 3-aminopropanamide SARDs that bind to LBD and the alternative binding and degradation domain (BDD; located in NTD), antagonize AR and destroy AR, thereby blocking ligand-dependent and ligand-independent AR activities. This new mechanism provides improved dosage efficacy systemically (for example, for prostate cancer) or topically (for example, dermatological diseases). X-linked spinal muscular atrophy of the spine (SBMA, also known as Kennedy's disease) is muscle atrophy that occurs due to a defect in the androgen receptor gene on the X chromosome. The proximal limb and bulbar muscle weakness in some cases lead to physical limitations, including wheelchair dependence. Mutation leads to a protraction of the polyglutamine pathway added to the N-terminal domain of the androgen receptor (polyQAR). The binding and activation of this extended polyQAR by endogenous androgens (testosterone and DHT) leads to the deployment and nuclear translocation of the mutant androgen receptor. These steps are necessary for pathogenesis and lead to a partial loss of transactivation function (i.e., insensitivity to androgens) and poorly understood neuromuscular degeneration. There is currently no disease-modifying treatment, but rather only targeted treatment of the symptoms. Efforts to target the polyQAR Kennedy disease as a proximal toxicity mediator using cellular equipment to stimulate its destruction, that is, through the use of SARD, promise therapeutic intervention. Selective androgen receptor destroyers, such as those described herein, bind and destroy various androgen receptors (full-size, splicing, antiandrogen-resistant mutants and probably also destroy polyQ AR polymorphisms), which indicates that they are promising for treatment SBMA.

SUMMARY OF THE INVENTION

In one embodiment, the present invention relates to a selective androgen receptor (SARD) compound represented by the structure of formula I:

I

Where

T represents OH, OR, -NHCOCH3or NHCOR;

Z represents NO2, CN, COOH, COR, NHCOR or CONHR;

Y represents CF3, F, I, Br, Cl, CN, C (R)3 or Sn (R)3;

R represents alkyl, haloalkyl, dihaloalkyl, trialoalkyl, CH2F, chf2CF3CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R1 represents CH3, CH2F, chf2CF3, CH2CH3, or CF2CF3;

R2 represents hydrogen, C1-C12-alkyl, -SO2-aryl, -SO2-phenyl, -CO-aryl, arylalkyl, substituted or unsubstituted benzyl, substituted or unsubstituted aryl, or C3-C7cycloalkyl;

Q1, Q2, Q3, Q4, and Q5 each independently selected from hydrogen, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CF3, CN, NO2, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted arylalkyl, C (R)3, N (R)2NHCOCH3NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3NHCSCF3, NHCSR, NHSO2CH3NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, or OCN;

where at least two Q1, Q2, Q3, Q4, and Q5 do not represent hydrogen; or

Q1 and Q2 linked together to form substituted or unsubstituted C5-C8 carbocyclic or heterocyclic rings, and Q3, Q4 and Q5represent, as defined above; or

Q2 and Q3 linked together to form substituted or unsubstituted C5-C8 carbocyclic or heterocyclic rings, and Q1, Q4 and Q5 represent, as defined above; and wherein said carbocyclic or heterocyclic ring formed is not dihydropyridin-2 (1H) -one, pyridin-2 (1H) -one or 1H-pyrrole.

In another embodiment of the invention, the selective androgen receptor destroyer (SARD) compound is represented by the structure of formula III:

III

Where

Z represents NO2 or CN;

Y represents CF3F, I, Br, Cl, or CN;

R2 represents hydrogen, C1-C12-alkyl, -SO2-aryl, -SO2-phenyl, -CO-aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted benzyl, substituted or unsubstituted aryl, or substituted or unsubstituted C3-C7cycloalkyl;

Q1, Q2 and Q3 each independently selected from hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, substituted or unsubstituted arylalkyl, F, Cl, Br, I, CF3, CN, NO2substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl;

where at least one of Q1, Q2 and Q3 represents substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted phenyl;

Q1 and Q2 linked together to form substituted or unsubstituted C5-C8a carbocyclic or heterocyclic ring, and Q3 represents, as defined above;

Q2 and Q3 linked together to form substituted or unsubstituted C5-C8 carbocyclic or heterocyclic rings, and Q1 represents, as defined above; and

wherein said carbocyclic or heterocyclic ring formed is not dihydropyridin-2 (1H) -one, pyridin-2 (1H) -one or 1H-pyrrole.

In one embodiment of the invention, the present invention relates to a compound of a selective androgen receptor destroyer (SARD) represented by the structure of formula IV:

IV

Where

T represents OH, OR, -NHCOCH3or NHCOR;

Z represents NO2, CN, COOH, COR, NHCOR or CONHR;

Y represents CF3, F, I, Br, Cl, CN, C (R)3 or Sn (R)3;

R represents alkyl, haloalkyl, dihaloalkyl, trialoalkyl, CH2F, chf2CF3CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R1 represents CH3, CH2F, chf2CF3, CH2CH3, or CF2CF3;

Q1 represents hydrogen, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CF3, CN, NO2, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted arylalkyl, C (R)3, N (R)2NHCOCH3NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3NHCSCF3, NHCSR, NHSO2CH3NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, or OCN;

Q2 represents hydrogen, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CF3, CN, NO2, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted arylalkyl, C (R)3, N (R)2NHCOCH3NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3NHCSCF3, NHCSR, NHSO2CH3NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, or OCN;

Q1 and Q2linked together to form substituted or unsubstituted C5-C8 carbocyclic or heterocyclic rings.

In one embodiment of the invention, the present invention relates to a compound of a selective androgen receptor destroyer (SARD) represented by the structure of formula VII:

VII

Where

T represents OH, OR, -NHCOCH3or NHCOR;

Z represents NO2, CN, COOH, COR, NHCOR or CONHR;

Y represents CF3, F, I, Br, Cl, CN, C (R)3or Sn (R)3;

R represents alkyl, haloalkyl, dihaloalkyl, trialoalkyl, CH2F, chf2CF3CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R1: CH3, CH2F, chf2CF3, CH2CH3, or CF2CF3; and

In another embodiment of the invention, Q1 Formulas I, III, IV, or VII is CN. In another embodiment of the invention, Q2 and Q3 of formulas III and IV are joined together to form a substituted or unsubstituted C5-C8a carbocyclic or heterocyclic ring. In another embodiment of the invention, Q1 formula VII is F or NO2.

In another embodiment, the SARD compound of the present invention is represented by the structure of any of the following compounds:

In another embodiment, the compound of the present invention binds to AR via an alternative binding and degradation domain (BDD). In another embodiment, some of the compounds of the present invention additionally bind an AR ligand of a binding domain (LBD). In another embodiment, the compound exhibits degradation activity of AR splicing (AR-SV). In another embodiment, the compound further exhibits AR-full-length degradation activity (AR-FL). In another embodiment, the compound exhibits an inhibitory activity of AR-SV (i.e., is an antagonist of AR-SV). In another embodiment, the compound further exhibits an AR-FL inhibitory activity (i.e., is an AR-FL antagonist). In another embodiment, the compound has dual AR-SV degradation and AR-SV inhibitory functions. In another embodiment, the compound further has dual AR-FL degradation and AR-FL inhibitory functions.

In one embodiment of the invention, the present invention relates to a pharmaceutical composition comprising a SARD compound of the present invention or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof, and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition is formulated for topical administration. In another embodiment, the pharmaceutical composition is in the form of a solution, lotion, ointment, cream, rub, liposome, spray, gel, foam, roller stick, cleansing soap or bar, emulsion, mousse, aerosol, shampoo, or any combination thereof.

In one embodiment of the invention, the present invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of prostate cancer (PCa) and its symptoms, or increasing the survival rate of a male subject suffering from prostate cancer, including administering to the subject subject therapeutically an effective amount of a compound of the present invention or its isomer, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof. In another embodiment, the prostate cancer is progressive prostate cancer, castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), high-risk nmCRPC, or any combination thereof. In one embodiment of the invention, the present invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of progressive prostate cancer and its symptoms, or increasing the survival of a male subject suffering from progressive prostate cancer, including administering to a specified subject a therapeutically effective amount of a compound of the present invention or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof.

In one embodiment, the present invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of castration-resistant prostate cancer (CRPC) and its symptoms, or increasing the survival rate of a male subject suffering from castration-resistant prostate cancer , comprising administering to said subject a therapeutically effective amount of a compound of the present invention or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof.

In another embodiment, prostate cancer is dependent on AR-SV for proliferation. In another embodiment, prostate cancer is further dependent on AR-FL for proliferation. In another embodiment, AR-SV is AR-V7 or ARv567es. In another embodiment, prostate cancer depends on an AR that contains a W741L mutation or a T877A mutation, or other anti-androgen resistance to AR-LBD mutations, or any combination thereof. In another embodiment, prostate cancer is dependent on the amplification of the AR gene in the tumor. In another embodiment of the invention, there may be heterogeneous expression of AR, so that prostate cancer may depend on multiple variations of AR and / or amplifications within the same patient. In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the subject has not undergone androgen deprivation therapy (ADT). In another embodiment, the cancer is resistant to treatment with an androgen receptor antagonist. In another embodiment, the androgen receptor antagonist is enzalutamide, flutamide, bicalutamide, abirator, ARN-509, AZD-3514, galeron, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, or any combinationolone. In another embodiment, administration of the compound reduces levels of AR, AR-full length (AR-FL), anti-androgen resistance AR-FL, AR-LBD mutations associated, AR-splicing variant (AR-SV), gene-amplified AR, or any combination of them, the specified subject.

In one embodiment of the invention, the present invention relates to a method for reducing levels of AR splicing variants in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof. In another embodiment of the invention, the method further reduces the levels of AR-full length in the specified subject. In another embodiment, recovery is achieved through degradation, inhibition, or double degradation and the inhibitory function of AR splicing (AR-SV) or AR-FL variants, including angiotensin resistance mutants such as W741L and T877A. In another embodiment, the reduction is further achieved by degradation, inhibition or double degradation and the inhibitory function of AR-FL. In another embodiment, recovery is further achieved by degradation or inhibition of AR from the amplified AR gene in the tumor.

In one embodiment of the invention, the present invention is directed to a method: (a) treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of acne in a subject; (b) a decrease in the production of sebum in a subject; (c) treating, suppressing, reducing the incidence of the disease, reducing the severity or inhibiting the progression of excessive hair growth in a subject; (d) treating, suppressing, reducing the incidence of the disease, reducing the severity or inhibiting the progression of alopecia in a subject; (e) treating, suppressing, reducing the incidence of the disease, reducing the severity or inhibiting the progression of the hormonal state in women; f) treating, suppressing, reducing the incidence of the disease, reducing the severity or inhibiting the progression of sexual perversions, hypersexuality, or paraphilia in a subject; (g) treating, suppressing, reducing the incidence of the disease, reducing the severity or inhibiting the progression of androgen psychosis in a subject; (h) treating, suppressing, reducing the incidence of the disease, reducing the severity or inhibiting the progression of virilization in a subject; (i) treating, suppressing, reducing the incidence of the disease, reducing the severity or inhibiting the progression of androgen insensitivity syndrome in a subject; (j) increasing, modulating, or improving ovulation in an animal; (k) treating, suppressing, reducing the incidence of the disease, reducing the severity or inhibiting the progression of cancer in a subject; or any combination thereof comprising administering a compound of the present invention or a pharmaceutical composition thereof.

In one embodiment of the invention, the present invention is directed to a method for reducing the levels of polyglutamine (polyQ) AR polymorphs in a subject, comprising administering a compound of the present invention. In another embodiment, recovery is achieved by degradation, inhibition or double degradation and inhibitory function of said polyglutamines (polyQ) AR polymorphs (polyQ-AR). In another embodiment, the polyQ-AR is a short polyQ polymorph or a long polyQ polymorph. In another embodiment, polyQ-AR is a short polyQ polymorph, and this method further treats skin disease. In another embodiment, polyQ-AR is a long polyQ polymorph, and the method further treats Kennedy's disease.

In one embodiment, the present invention is directed to a method for treating, suppressing, reducing the incidence, reducing the severity or inhibiting the progression of amyotrophic lateral sclerosis (ALS) in a subject, comprising administering a therapeutically effective amount of a compound of the present invention or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutical product, polymorph, hydrate, or any combination thereof; or its pharmaceutical composition.

In one embodiment of the invention, the present invention is directed to a method for treating, suppressing, reducing the incidence, reducing the severity or inhibiting the progression of uterine fibroids in a subject, comprising administering a therapeutically effective amount of a compound of the present invention or isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof; or its pharmaceutical composition.

A brief description of the graphic materials

The subject matter considered as an invention is specifically indicated and clearly stated in the final part of the specification. The invention, however, both to the organization and to the way of working with objects, features and advantages, can be best understood with reference to the following detailed description when reading with the attached graphic materials on which:

Figure 1 shows the effect of new AR antagonists on AR protein levels (i.e., the SARD effect). (A) Serum-free LNCaP cells were treated with R1881 and SARD compound (17). (B) Dose response (17) in the presence of 0.1 nM R1881 in LNCaP cells. (C) LNCaP cells were seeded in pure serum and treated with compound (17) (dose response). Cells were harvested, the protein was extracted, and Western blotting was performed for AR and actin. (D) Effect of (17) on wild-type AR transfected into HeLa cells. (E) The effect of (14) on the expression of AR in VCaP. (F) AR response to SARD (14) in LNCaP cells. 17-AAG-17-allylamino-17-demethoxygeldanamycin, an Hsp90 inhibitor. MDV-3100, an AR antagonist (antiandrogen), also known as enzalutamide. AR - androgen receptor; R1881 - An agonist of AR.

Figure 2A and Figure 2B depict the destruction of AR compound SARD (17) in LNCaP cells. (A) LNCaP cells were seeded in serum-free medium and treated with the indicated concentrations of compound (17) and ARN-509 in the presence or absence of R1881. Cells were harvested, the protein was extracted, and Western blotting was performed for AR and actin. (B) LNCaP cells were seeded in 96-well plates at 10,000 cells / well in RPMI + 1% csFBS without phenol red. Cells were treated as described above, in combination with 0.1 nM R1881 for 6 days with a change in medium on day 3. After 6 days, the cells were fixed and stained with sulforodamine blue to measure cell growth. Enzalutamide and ARN-509 are other AR antagonists that are reported to degrade AR.

Figure 3 depicts the effect of SARD on AR-FL and AR-SV protein levels. (A) and (B) SARD (17) degrades the full-length AR and splicing variant in 22RV-1 cells. 22RV-1 cells were seeded in serum-free medium and treated with the indicated concentrations of compound (17), ARN-509 or ASC-J9 in the presence or absence of R1881. Cells were harvested, the protein was extracted, and Western blotting was performed for AR and actin. Spots were quantified using Image-J (panel B). (C) The same experiment was repeated with compound (14). AR-FL - full length androgen receptor; AR-V7 - splicing variant of androgen receptor 7 (no ligand binding domain); ARN-509 and ASC-J9 are other AR antagonists that are reported to degrade AR

4 shows AR degradation by SARD under varying conditions (AD) without destroying other receptors (EF). (A) and (B) LNCaP cells were serum-free and treated with compound 17 (10 μM in panel A and dose response in panel B) in the presence or absence of R1881. Bicalutamide was used as a negative control. Cells were harvested, the protein was extracted, and Western blotting was performed for AR and actin. (C) LNCaP cells were seeded in pure serum and treated with compound 17 (dose response). Cells were harvested, the protein was extracted, and Western blotting was performed for AR and actin. (D) HeLa cells were infected with an adenovirus containing AP and treated with compound 17 in the presence or absence of R1881. Cells were harvested, the protein was extracted, and Western blotting was performed for AR and actin. (E) and (F) SARD do not degrade other nuclear receptors. T47D cells (left panel) and MCF-7 (right panel) were seeded in pure serum and treated with compound 17 (dose response). Cells were harvested, the protein was extracted and Western blotting was performed for PR (progesterone receptor) or ER-α (estrogen-alpha receptor) and actin.

Figure 5 shows the effect of SARD (17) and (14) on the tissue of an AR target (SV or SV - seminal vesicles and prostate gland) in a Gershberger analysis. The numbers at the bottom of the diagrams represent the area under the curve (AUC) for the concentration of the drug.

Figure 6 shows that SARDs do not inhibit the transactivation of other receptors up to 10 μM. HEK-293 cells were transfected with the indicated receptors and GRE-LUC and CMV-renillalus. Cells were treated (17) for 24 hours after transfection and luciferase analysis was performed 48 hours after transfection. GR - glucocorticoid receptor; Dex - dexamethasone; MR - mineralocorticoid receptor; Ald - aldosterone; PR - progesterone receptor; and Prog is progesterone.

Figure 7 shows that SARD treatment inhibited AR recruitment of androgen sensitive genes (PSA, FKBP and TMPRSS2) to the promoter, and lowered core AR levels in R1881 treated animals. (A) LNCaP cells were serum-separated for 3 days and treated as described above with SARD (17) or bicalutamide at 10 μM in the presence or absence of 0.1 nM R1881. Proteins were crosslinked with DNA, and chromatin immunoprecipitation studies were performed with AR and RNA-PolII antibodies. (B) SARD impair AR. LNCaP cells were serum-free for 3 days and treated as described above with SARD (17) at 10 μM in the presence or absence of 0.1 nM R1881. Cells were fixed and immunofluorescence was performed for AR. The nucleus was stained with DAPI.

Figure 8 shows that SARDs inhibit the growth of LNCaP cells by non-competitive binding of AR. LNCaP cells were seeded in serum-free medium and treated with an increase in the concentration of enzalutamide or compound 17 in the presence of a dose range of R1881. Seven days after treatment, the cells were fixed and growth was measured using a WST-1 assay.

Figure 9 shows that 49 in the presence of R1881 degrades AR in LNCaP cells. LNCaP cells were seeded in 6-well plates with 1 million cells / well. Cells were kept under serum-free conditions for 3 days. Cells were processed as indicated in the figure, collected, the protein was extracted and Western blotting was performed for AR. 49 (and other SARDs described here) demonstrated selective AR degradation (i.e., SARD activity) in the nM range, i.e., in concentrations comparable to their IC values50 antagonist. LNCaP cells are known to express the T877A AR mutant, demonstrating the ability of the SARD of the present invention to degrade the antiandrogen resistance giving mutant androgen receptors.

Figure 10 shows that 49 destroys AR in RV22-1 cells. 22RV-1 cells were seeded in a 6-well plate at 1-1.5 million cells / well in growth medium (RPMI + 10% FBS). The next day, the medium was changed and treated with a carrier medium or a dose response of 49. After overnight treatment (12-16 hours), the cells were washed in ice-cold PBS and collected by separation in 1 ml of PBS. The cells were granulated, the protein was extracted, quantified using BCA analysis, and an equal amount of protein was fractionated on SDS-PAGE. Proteins were transferred onto a nylon membrane and Western blotted with an AR antibody (N20 from SCBT) and an actin antibody. 49 (and the other SARDs described here) are capable of degrading the full length androgen receptor (AR-FL) and clipped AR (AR-SV) in 22RV-1 cells, indicating that the SARDs of the present invention can overcome AR-V7 dependent cancers diseases of the prostate gland.

Figure 11 shows that SARDs bind to the N-terminal activation function 1 AR (AR-AF1) in addition to the C-terminal ligand binding domain (LBD), which contains AR-AF2. Figure 11A: There are two tryptophan residues and up to 12 tyrosine residues. This allowed us to study the bending properties of this domain using internal stable states of fluorescence emission spectra. Excitation at 287 nm excites tyrosine and tryptophan residues. The maximum radiation (λmax) for tryptophan is sensitive to solvent exposure. In the presence of the natural osmolyte TMAO (AF1 + TMAO), a characteristic “blue shift” is observed, which is consistent with tryptophan residues, which are less exposed to the solvent, and shoulder loss (~ 307 nm, see a solid black trace compared to AF1 (one), which is the second from the top at 300 nm in the left panel and the top trace at 300 nm in the right panel) for tyrosine, since in the case of addition of polypeptides, the energy transfer to tryptophan increases. On the contrary, in the presence of urea (unfolding occurs), a “red shift” occurs when the tryptophan residues become more soluble and a certain peak appears for the release of tyrosine. To check whether the compounds (enobosarm (E) and 17) interact with AF-1 and / or change the flexion of this domain, we measured the steady state fluorescence for each compound only with AR-AF1 or the presence of TMAO (3 M) or urea (4 or 6 M). Enobosarm was used as a negative control (should not interact), while TMAO served as a positive control (should facilitate bending). We used 1 μM AR-AF1 and 5 μM individual compounds and were preincubated for at least 30 minutes before measuring the emission spectra. Emission spectra were adjusted only for the buffer or buffer with TMAO / urea / compounds as necessary. There was no dramatic effect of enobosarm (left panel) on λmax for tryptophan, and 17 (right panel) reduces the wavelength (i.e. “Blue shift”), which indicates that 17 binds to AF-1 and enobosarm does not bind to AF-1. Also, the shoulder is absent in the AF1 + TMAO + 17 curve. Figure 11B: Left panel: dose-dependent fluorescence intensity shift (ie, quenching) for 17 was observed during incubation with ARAF-1. The fluorescence arm was observed at 307 nm, which corresponds to the tyrosine residues in AF-1, shifted for 17. The total fluorescence also varies markedly for 17. This indicates that 17 interacts with ARAF-1 (in addition to LBD, demonstrated in other experiments). Right panel. The data shown in the left panel were displayed as the difference in the fluorescence graph between the treated control samples and 17 (fluorescence in the absence of compound - fluorescence in the presence of compound), the dose increase depended on the presence of 17, again showing that 17 interacts with ARAF-1. AF1 - activation function-1, which is a domain in NTDAR; TMAO - trimethylamine-N-oxide; E - enobosarm, which is a selective modulator of the androgen receptor that does not bind to NTD; 17 is a selective androgen receptor disruptor (SARD) of the present invention.

The figure 12 shows the initial data of bio isolation - interferometry (BLI) of the binding of AF1 with compound 17 at a concentration of 50 nm. The first 60 seconds are basic (do not start at 0), and then 300 seconds are the phases of association and dissociation (~ 1650 - 1950 along the Y axis). The loadable AF1 biosensors are the top two curves. Adding 17 to the loaded AF-1 layers causes a greater bias compared to controls loaded with ERD14 and biocytin (bottom two curves) as reference sensors, suggesting that 17 has a direct interaction with AF-1 at concentrations up to 50 nM.

It is understood that for simplicity and clarity of illustration, the elements shown in the graphic materials need not be drawn to scale. For example, the dimensions of some elements may be exaggerated compared to other elements for clarity. Furthermore, if deemed appropriate, reference numerals may be repeated among the figures to indicate corresponding or similar elements.

Detailed Description of the Invention

In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention.

Androgens act in cells by binding to AR, a member of the superfamily of steroid receptor transcription factors. Since the growth and content of prostate cancer (RSA) is largely controlled by circulating androgens, treatment of RSA is largely dependent on treatment methods that target AR. Treatment with AR antagonists, such as enzalutamide, flutamide, bicalutamide or hydroxyflutamide, to impair receptor activation, has been used successfully in the past to reduce PCa growth. All currently available AR antagonists are competitively linked to AR and attract corepressors such as NCoR and SMRT to suppress transcription of target genes. However, altered intracellular signaling, AR mutations, and increased expression of coactivators lead to functional impairment of antagonists or even transformation of antagonists into agonists. Studies have shown that the W741 and T877 mutations within AR convert bicalutamide and hydroxyflutamide, respectively, into agonists. Similarly, increased intracellular cytokines attract coactivators instead of corepressors for AR-responsive promoters, subsequently converting bicalutamide into an agonist.

Despite the initial response to androgen deprivation therapy (ADT), the progression of PCa disease is inevitable, and the cancer occurs as castration-resistant prostate cancer (CRPC). The primary cause of the reappearance of castration-resistant prostate cancer (CRPC) is the reactivation of androgen receptor (AR) via alternative mechanisms, such as:

intracrine synthesis of androgens;

expression of AR splicing variants (AR-SV) that do not have a ligand binding domain (LBD);

mutations AR-LBD, able to withstand antagonists;

hypersensitivity of AR to low levels of androgens, for example, due to amplification of the AR gene or AR mutations;

amplification of the AR gene in the tumor; and

overexpression of coactivators.

In one embodiment of the invention, the present invention relates to new compounds of selective androgen receptor destroyers (SARDs) that inhibit the growth of prostate cancer cells (PCA) and tumors that depend on the full length of AR (AR-FL), including pathogenic and resistant-comparable mutation and / or wild-type and / or variants of AR-splicing (AR-SV) for proliferation.

In accordance with the present invention, the Androgen Receptor Selective Disruptor (SARD) compound is an androgen receptor antagonist that is able to inhibit the growth of PCA cells and tumors that depend on the full length of AR (AR-FL) and / or AR splicing (AR) variants -SV) for proliferation. In another embodiment, the SARD compound does not bind to the ligand binding domain (LBD). In another embodiment, the SARD compound binds to the N-terminal domain (NTD) AR. In another embodiment, the SARD compound binds to an alternate AR binding and degradation domain (BDD). In another embodiment, the SARD compound binds to both the AR ligand binding domain (LBD) and the alternative binding and degradation domain (BDD). In another embodiment, the SARD compound binds to both the N-terminal domain (NTD) and the ligand binding domain (LBD) AR. In another embodiment, the SARD compound is capable of inhibiting N-terminal domain (NTD) -dependent constitutively active AR-SV growth. In another embodiment, the SARD compound inhibits AR by binding to a domain that is different from ARLBD. In another embodiment, the SARD compound is a strong (i.e. potent and highly potent) selective androgen receptor antagonist that counteracts AR more than other known AR antagonists (e.g. enzalutamide, flutamide, bicalutamide and abirator). In another embodiment, the SARD compound is a selective androgen receptor antagonist that targets AR-SVs that cannot be inhibited by conventional antagonists. In another embodiment, the SARD compound exhibits degradation activity of an AR splicing variant (AR-SV). In another embodiment, the SARD compound further exhibits degradation activity of AR-full length (AR-FL). In another embodiment, the SARD compound exhibits the inhibitory activity of an AR splicing variant (AR-SV) (i.e., an AR-SV antagonist). In another embodiment, the SARD compound further exhibits AR-full length inhibitory activity (AR-FL) (i.e., is an AR-FL antagonist). In another embodiment, the SARD compound has dual AR-SV degradation and AR-SV inhibitory functions. In another embodiment, the SARD compound further has dual AR-FL degradation and AR-FL inhibitory functions. In another embodiment, the SARD compound is a selective androgen receptor antagonist that targets AR-SV. In another embodiment, the SARD compound further targets AR-FL. In another embodiment, the SARD compound inhibits the constitutive activation of AR-SV. In another embodiment, the SARD compound further inhibits the constitutive activation of AR-FL. In another embodiment, the SARD compound is a selective androgen receptor antagonist that destroys full-length AR (AR-FL) and AR-splicing variants (AR-SV). In another embodiment, the SARD compound destroys AR by binding to a domain that is different from ARLBD. In another embodiment, the SARD compound has dual degradation and AR-SV inhibitory functions that are different from any available CRPC therapies. In another embodiment, the SARD compound inhibits AR reactivation by alternative mechanisms, such as intracrine androgen synthesis, expression of AR splicing variants (AR-SV) that do not have ligand binding domain (LBD) mutations and AR-LBD with potential antagonist antagonists . In another embodiment, the SARD compound inhibits the reactivated androgen receptors present in pathologically altered cell media.

Non-limiting examples of AR splicing options (AR-SV) are: AR-V7 and ARv567es (aka AR-V12). Non-limiting examples of AR mutations providing antiandrogen resistance are: W741L mutation and T877A mutation. AR-V7 is an AR splicing option that lacks LBD. It is constitutively active and has been shown to be responsible for aggressive RSA and resistance to endocrine therapy.

In one embodiment, the present invention provides novel androgen receptor selective disruptor (SARD) compounds that bind to AR via an alternative binding and degradation domain (BDD). In another embodiment, the SARD further binds the AR ligand binding domain (LBD).

In one embodiment, the present invention provides novel androgen receptor selective destroyer (SARD) compounds that exhibit the inhibitory activity of an AR splicing variant (AR-SV) (i.e., an AR-SV antagonist). In another embodiment, the novel Androgen Receptor Selective Destroyer (SARD) compounds further exhibit AR-full length (AR-FL) inhibitory activity (i.e., an AR-FL antagonist).

In one embodiment of the invention, the present invention relates to new compounds of selective androgen receptor disruptors (SARDs) that exhibit the degrading activity of an AR splicing variant (AR-SV). In another embodiment, the novel Androgen Receptor Selective Compound (SARD) compounds further exhibit the degrading activity of AR-full length (AR-FL).

In one embodiment of the invention, the present invention relates to new compounds of selective androgen receptor destroyers (SARDs), which exhibit double AR-SV degradation and AR-SV inhibitory functions. In another embodiment, the SARDs additionally have the functions of dual AR-FL degradation and AR-FL inhibition. In another embodiment of the invention, the present invention relates to new compounds of selective androgen receptor destroyers (SARD), which exhibit double degradation of AR-SV and AR-FL, as well as inhibitory functions of AR-SV and AR-FL.

In one embodiment of the invention, the present invention relates to new compounds of selective androgen receptor disruptors (SARDs), for use in the treatment of CRPC that cannot be treated by any other antagonist.

In one embodiment of the invention, the present invention relates to new compounds of selective androgen receptor disruptors (SARDs), for use in the treatment of CRPC, by reducing AR-SV.

In one embodiment, the novel SARD compounds of the present invention support their antagonistic activity in AR mutants, which typically convert AR antagonists into agonists. In another embodiment, the SARD compounds retain their antagonistic activity with the W741 and T877 AR mutants. In another embodiment, SARD compounds induce antagonistic activity in an altered cell medium in which LBD target agents are not effective. In another embodiment of the invention, SARD compounds induce antagonistic activity in an altered cell medium in which NTD activity-dependent activity is constitutively active.

Selective Androgen Receptor Destroyer (SARD) Compounds

In one embodiment of the invention, the present invention relates to a compound of selective androgen receptor disrupters (SARD) represented by the structure of formula I:

I

Where

T represents OH, OR, -NHCOCH3or NHCOR;

Z represents NO2, CN, COOH, COR, NHCOR or CONHR;

Y represents CF3, F, I, Br, Cl, CN, C (R)3 or Sn (R)3;

R represents alkyl, haloalkyl, dihaloalkyl, trialoalkyl, CH2F, chf2CF3CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R1 represents CH3, CH2F, chf2CF3, CH2CH3, or CF2CF3;

R2 represents hydrogen, C1-C12-alkyl, -SO2-aryl, -SO2phenyl, -CO-aryl, arylalkyl, benzyl, aryl or C3-C7cycloalkyl;

Q1, Q2, Q3, Q4 and Q5 each independently selected from hydrogen, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CF3, CN, NO2, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted arylalkyl, C (R)3, N (R)2NHCOCH3NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3NHCSCF3, NHCSR, NHSO2CH3NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, or OCN;

where at least two of Q1, Q2, Q3, Q4 and Q5 do not represent hydrogen; or

Q2 and Q3 connected together to form a substituted or unsubstituted C5-C8 carbocyclic or heterocyclic ring, and Q1, Q4 and Q5 are as defined above; and

wherein said carbocyclic or heterocyclic ring formed is not dihydropyridin-2 (1H) -one, pyridin-2 (1H) -one or 1H-pyrrole.

In one embodiment of the invention, the present invention relates to a compound of selective androgen receptor disrupters (SARD) represented by the structure of formula II:

II

Where

T represents OH, OR, -NHCOCH3or NHCOR;

Z represents NO2, CN, COOH, COR, NHCOR or CONHR;

Y represents CF3, F, I, Br, Cl, CN, C (R)3 or Sn (R)3;

R represents alkyl, haloalkyl, dihaloalkyl, trialoalkyl, CH2F, chf2CF3CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R1 represents CH3, CH2F, chf2CF3, CH2CH3, or CF2CF3;

R2 represents hydrogen, C1-C12-alkyl, -SO2-aryl, -SO2phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C3-C7cycloalkyl;

Q3 represents hydrogen, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CF3, CN, NO2, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted arylalkyl, C (R)3, N (R)2NHCOCH3NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3NHCSCF3, NHCSR, NHSO2CH3NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, or OCN;

where at least two of Q1, Q2 and Q3 do not represent hydrogen; or

Q1 and Q2linked together to form substituted or unsubstituted C5-C8a carbocyclic or heterocyclic ring, and Q3 represents, as defined above; or

Q2 and Q3 linked together to form substituted or unsubstituted C5-C8a carbocyclic or heterocyclic ring, and Q1 is as defined above; and

wherein said carbocyclic or heterocyclic ring formed is not dihydropyridin-2 (1H) -one, pyridin-2 (1H) -one or 1H-pyrrole.

In one embodiment of the invention, the present invention relates to a compound for selective androgen receptor destroyers (SARD) represented by the structure of formula III

III

Where

Z represents NO2 or CN;

Y represents CF3F, I, Br, Cl, or CN;

R2 represents hydrogen, C1-C12-alkyl, -SO2-aryl, -SO2phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C3-C7cycloalkyl

Q1 represents substituted or unsubstituted aryl, substituted or unsubstituted phenyl, substituted or unsubstituted arylalkyl, CN or NO2;

Q2 represents hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CF3, CN, NO2substituted or

unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted arylalkyl;

Q3 represents hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CF3, CN, NO2, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted arylalkyl;

where at least one of Q2 and Q3 represents substituted or unsubstituted aryl, substituted or unsubstituted phenyl, or substituted or unsubstituted arylalkyl; or

Q2 and Q3linked together to form substituted or unsubstituted C5-C8 carbocyclic or heterocyclic rings, and Q1 represents, as defined above.

In another embodiment of the invention, the present invention relates to a compound of selective androgen receptor destroyers (SARD) represented by the structure of formula III:

III

Where

Z represents NO2 or CN;

Y represents CF3F, I, Br, Cl, or CN;

where at least one of Q1, Q2 and Q3 represents substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted phenyl;

Q1 and Q2 linked together to form substituted or unsubstituted C5-C8a carbocyclic or heterocyclic ring, and Q3 represents, as defined above;

Q2 and Q3 linked together to form substituted or unsubstituted C5-C8a carbocyclic or heterocyclic ring, and Q1 represents, as defined above; and

wherein said carbocyclic or heterocyclic ring formed is not dihydropyridin-2 (1H) -one, pyridin-2 (1H) -one or 1H-pyrrole.

In one embodiment of the invention, the present invention relates to a compound of selective androgen receptor disruptors (SARD) represented by the structure of formula IV:

IV

Where

T represents OH, OR, -NHCOCH3or NHCOR;

Z represents NO2, CN, COOH, COR, NHCOR or CONHR;

Y represents CF3, F, I, Br, Cl, CN, C (R)3 or Sn (R)3;

R represents alkyl, haloalkyl, dihaloalkyl, trialoalkyl, CH2F, chf2CF3CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R1 represents CH3, CH2F, chf2CF3, CH2CH3, or CF2CF3;

Q1 and Q2 linked together to form substituted or unsubstituted C5-C8a carbocyclic or heterocyclic ring.

In one embodiment of the invention, the present invention relates to a compound of selective androgen receptor disrupters (SARD) represented by the structure of formula V:

V

Where

T represents OH, OR, -NHCOCH3or NHCOR;

Z represents NO2, CN, COOH, COR, NHCOR or CONHR;

Y represents CF3, F, I, Br, Cl, CN, C (R)3 or Sn (R)3;

R represents alkyl, haloalkyl, dihaloalkyl, trialoalkyl, CH2F, chf2CF3CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R1 represents CH3, CH2F, chf2CF3, CH2CH3, or CF2CF3; and

In one embodiment of the invention, the present invention relates to a compound of selective androgen receptor disruptors (SARD) represented by the structure of formula VI:

VI

Where

T represents OH, OR, -NHCOCH3or NHCOR;

Z represents NO2, CN, COOH, COR, NHCOR or CONHR;

Y represents CF3, F, I, Br, Cl, CN, C (R)3 or Sn (R)3;

R represents alkyl, haloalkyl, dihaloalkyl, trialoalkyl, CH2F, chf2CF3CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R1 represents CH3, CH2F, chf2CF3, CH2CH3, or CF2CF3;

Q1 and Q2 linked together to form substituted or unsubstituted C5-C8a carbocyclic or heterocyclic ring.

In one embodiment of the invention, the present invention relates to a compound of selective androgen receptor disrupters (SARD) represented by the structure of formula VII:

VII

Where

T represents OH, OR, -NHCOCH3or NHCOR;

Z represents NO2, CN, COOH, COR, NHCOR or CONHR;

Y represents CF3, F, I, Br, Cl, CN, C (R)3 or Sn (R)3;

R represents alkyl, haloalkyl, dihaloalkyl, trialoalkyl, CH2F, chf2CF3CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R1 represents CH3, CH2F, chf2CF3, CH2CH3, or CF2CF3; and

In one embodiment of the invention, Q1 the compounds of formulas I-VII is CN. In another embodiment of the invention, Q1 represents F. In another embodiment of the invention, Q1 represents Cl. In another embodiment of the invention, Q1 represents Br. In another embodiment of the invention, Q1 represents I. In another embodiment of the invention, Q1 represents NO2. In another embodiment of the invention, Q1 represents H. In another embodiment of the invention, Q1 represents phenyl. In another embodiment of the invention, Q1 represents aryl. In another embodiment of the invention, Q1 represents arylalkyl. In another embodiment, the arylalkyl is benzyl. In another embodiment of the invention, Q1 represents 4-fluorophenyl.

In one embodiment of the invention, Q1 the compounds of formula III is CN. In another embodiment of the invention, Q1 represents phenyl. In another embodiment of the invention, Q1 represents aryl. In another embodiment of the invention, Q1 represents arylalkyl. In another embodiment, the arylalkyl is benzyl. In another embodiment of the invention, Q1 represents 4-fluorophenyl.

In one embodiment of the invention, Q1 the compounds of formulas VI or VII is F. In another embodiment of the invention, Q1 represents Cl. In another embodiment of the invention, Q1 represents Br. In another embodiment of the invention, Q1 is I. In another embodiment of the invention, Q1 represents NO2. In another embodiment of the invention, Q1 represents CN.

In one embodiment of the invention, Q2 the compounds of formulas I-IV and VI is CN. In another embodiment of the invention, Q2 represents H. In another embodiment of the invention, Q2 represents phenyl. In another embodiment of the invention, Q2 represents aryl. In another embodiment of the invention, Q2 represents arylalkyl. In another embodiment, the arylalkyl is benzyl. In another embodiment of the invention, Q2 represents 4-fluorophenyl.

In one embodiment of the invention, Q3 the compounds of formulas I-III is CN. In another embodiment of the invention, Q3 represents H. In another embodiment of the invention, Q3 represents phenyl. In another embodiment of the invention, Q3 represents aryl. In another embodiment of the invention, Q3 represents arylalkyl. In another embodiment, the arylalkyl is benzyl. In another embodiment of the invention, Q3 represents 4-fluorophenyl.

In one embodiment of the invention, Q1 and Q2 the compounds of formulas I-IV and VI are joined together to form substituted or unsubstituted C5-C8a carbocyclic or heterocyclic ring. In another embodiment, C5The —C8 carbocyclic ring is benzene. In another embodiment, the carbocyclic ring C5-FROM8 represents substituted benzene, where the substitution is one or more groups selected from halogen, haloalkyl, hydroxy, alkoxycarbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxy, thio or thioalkyl. In another embodiment of the invention, Q1 and Q2 represent - (CH)4-. In another embodiment, C5-C8 the heterocyclic ring is piperidine, pyridine, furan, thiophene, pyrrole, pyrrolidine, pyrazine, piperazine or pyrimidine.

In one embodiment of the invention, Q2 and Q3 compounds of formulas I-III are joined together to form substituted or unsubstituted C5-C8a carbocyclic or heterocyclic ring. In another embodiment, C5-C8The carbocyclic ring is benzene. In another embodiment, the carbocyclic ring C5-FROM8 represents substituted benzene, where the substitution is one or more groups selected from halogen, haloalkyl, hydroxy, alkoxycarbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxy, thio or thioalkyl. In another embodiment of the invention, Q2 and Q3 represent - (CH)4-. In another embodiment, C5-C8the heterocyclic ring is piperidine, pyridine, furan, thiophene, pyrrole, pyrrolidine, pyrazine, piperazine or pyrimidine.

In one embodiment of the invention, Q1 the compounds of formulas I-III is CN, Q2 represents phenyl and Q3 represents hydrogen. In another embodiment of the invention, Q1 represents CN, Q2 represents hydrogen and Q3 represents phenyl. In another embodiment of the invention, Q1 represents CN, and Q2 and Q3 bonded together to form a benzene ring (i.e., represent - (CH)4-).

In one embodiment of the invention, R2 the compounds of formulas I-III is alkyl. In another embodiment, R2 represents methyl. In another embodiment, R2 is ethyl. In another embodiment, R2 represents a cut. In another embodiment, R2 is isopropyl. In another embodiment, R2 represents pentyl. In another embodiment, R2 represents hexyl. In another embodiment, R2 represents C3-C7cycloalkyl. In another embodiment, R2 represents cyclobutyl. In another embodiment, R2 represents benzyl. In another embodiment, R2 represents methylcyclohexyl. In another embodiment, R2 represents CO-phenyl. In another embodiment, R2 represents SO2-phenyl. In another embodiment, R2 represents SO2phenyl OCH3. In another embodiment, R2 represents SO2phenyl-F.

In one embodiment, the Z compound of Formulas I-VII is CN. In another embodiment, Z is NO.2. In another embodiment, Z is COOH. In another embodiment, Z is COR. In another embodiment, Z is NHCOR. In another embodiment, Z is CONHR.

In one embodiment of the invention, the Y compound of formulas I-VII is CF3. In another embodiment, Y is F. In another embodiment, Y is I. In another embodiment, Y is Br. In another embodiment, Y is Cl. In another embodiment, Y is CN. In another embodiment, Y is C (R)3. In another embodiment, Y is Sn (R)3.

In one embodiment, Z of the compound of Formulas I-VII is CN and Y is CF3. In another embodiment, Z is NO.2 and Y is CF3. In another embodiment, Z is NO.2 and Y is halogen. In another embodiment, Z is CN and Y is halogen.

In one embodiment of the invention, R1 the compounds of formulas I-II and IV-VII is CH3. In another embodiment, R1 represents CF3.

In one embodiment, the T of the compound of formulas I-II and IV-VII is OH. In another embodiment, T is OCH3.

In one embodiment, R of the compound of formula I-II and IV-VII is alkyl. In another embodiment, R is haloalkyl. In another embodiment of the invention, R is dihaloalkyl. In another embodiment, R is trihaloalkyl. In another embodiment, R is CH2F. In another embodiment, R is CHF2. In another embodiment, R is CF3. In another embodiment, R is CF2CF3. In another embodiment, R is aryl. In another embodiment, R is phenyl. In another embodiment, R is F. In another embodiment, R is Cl. In another embodiment, R is Br. In another embodiment, R is I. In another embodiment, R is alkenyl. In another embodiment, R is hydroxyl (OH).

In one embodiment, the present invention relates to a selective androgen receptor (SADR) compound, any one of the following structures:

The term “carbocyclic ring” means either a saturated, unsaturated or aromatic ring consisting solely of carbon atoms.

The term “heterocyclic group” refers, in one embodiment, to a ring structure containing, in addition to carbon atoms, sulfur, oxygen, nitrogen atoms, or any combination thereof as part of the ring. In another embodiment, the heterocycle is a 3-12 membered ring. In another embodiment, the heterocycle is a 6 membered ring. In another embodiment, the heterocycle is a 5-7 membered ring. In another embodiment, the heterocycle is a 4-8 membered ring. In another embodiment, the heterocyclic group may be unsubstituted or substituted with halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO2H, amino, alkylamino, dialkylamino, carboxyl, thio and / or thioalkyl. In another embodiment, the heterocyclic ring may be fused to another saturated or unsaturated cycloalkyl or heterocyclic 3-8 membered ring. In another embodiment, the heterocyclic ring is a saturated ring. In another embodiment, the heterocyclic ring is an unsaturated ring. In another embodiment, the heterocycle is piperidine. In another embodiment, the heterocycle is pyridine. In another embodiment, the heterocycle is piperidine, pyridine, furan, thiophene, pyrrole, pyrrolidine, pyrazine, piperazine or pyrimidine.

The term “cycloalkyl” refers to a non-aromatic, monocyclic or polycyclic ring containing carbon and hydrogen atoms. The cycloalkyl group may have one or more carbon-carbon double bonds in the ring until the ring becomes aromatic in their presence. Examples of cycloalkyl groups include, but are not limited to, (C3-C7) cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and saturated cyclic and bicyclic terpenes, and (C3-C7) cycloalkenyl groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl, and unsaturated cyclic and bicyclic terpenes. The cycloalkyl group may be unsubstituted or substituted with one or two substituents. Preferably, the cycloalkyl group is a monocyclic ring or a bicyclic ring.

Non-limiting Examples for "C5-C8 "carbocyclic or heterocyclic rings" are carbocyclic rings such as cyclopentane, cyclopentene, cyclohexane, benzene and cyclohexene rings and heterocyclic rings such as pyran, dihydropyran, tetrahydropyran, dihydropyridine, tetrazidiridine, pyrazine, pyrazine, pyrazine, pyrazine. pyrazole, dihydropyrazole, tetrahydropyrazole, piperidine, piperazine, pyridine, dihydropyridine, tetrahydropyridine, morpholine, thiomorpholine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, thiazole, imidazole, isoxazole and the like.

In one embodiment, the term “alkyl” refers to a saturated aliphatic hydrocarbon, including linear, branched, and cyclic alkyl groups. In one embodiment, the alkyl group has 1-12 carbon atoms. In another embodiment, the alkyl group has 1-7 carbon atoms. In another embodiment, the alkyl group has 1-6 carbon atoms. In another embodiment, the alkyl group contains 1-4 carbon atoms. In another embodiment, the cyclic alkyl group has 3-8 carbon atoms. In another embodiment, the cyclic alkyl group has 3-12 carbon atoms. In another embodiment, branched alkyl is alkyl substituted with 1 to 5 carbon atoms with alkyl side chains. In another embodiment, branched alkyl is alkyl substituted with haloalkyl with side chains of 1 to 5 carbon atoms. The alkyl group may be unsubstituted or substituted with halogen, haloalkyl, hydroxyl, alkoxycarbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and / or thioalkyl.

An “arylalkyl” group refers to alkyl bound to aryl, where alkyl and aryl are as defined above. An example of an arylalkyl group is a benzyl group.

In another embodiment, an “alkenyl” group refers to an unsaturated hydrocarbon, including linear, branched and cyclic groups having one or more double bonds. An alkenyl group may have one double bond, two double bonds, three double bonds, etc. In another embodiment, the alkenyl group has 2-12 carbon atoms. In another embodiment, the alkenyl group has 2-6 carbon atoms. In another embodiment, the alkenyl group has 2-4 carbon atoms. Examples of alkenyl groups are ethenyl, propenyl, butenyl, cyclohexenyl, etc. The alkenyl group may be unsubstituted or substituted with halogen, hydroxy, alkoxycarbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and / or thioalkyl.

An “aryl” group refers to an aromatic group having at least one carbocyclic aromatic group or heterocyclic aromatic group, which may be unsubstituted or substituted by one or more groups selected from halogen, haloalkyl, hydroxy, alkoxycarbonyl, amido, alkylamido, dialkylamido, nitro , amino, alkylamino, dialkylamino, carboxy or thio or thioalkyl. Non-limiting examples of aryl rings are phenyl, naphthyl, pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl, furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl and the like. In one embodiment, the aryl group is a 4-8 membered ring. In another embodiment, the aryl group is a 4-12 membered ring (s). In another embodiment, the aryl group is a 6 membered ring. In another embodiment, the aryl group is a 5 membered ring. In another embodiment, the aryl group is a 2-4 fused ring system.

An “aldehyde” group in one embodiment refers to an alkyl or alkenyl substituted with a formyl group, wherein the alkyl or alkenyl is as defined above. In another embodiment, the aldehyde group is an aryl or phenyl group substituted with a formyl group, wherein the aryl is as defined above. Examples of aldehydes are: formyl, acetal, propanal, butanal, pentanal, benzaldehyde. In another embodiment, the aldehyde group is a formyl group.

A “haloalkyl” group in another embodiment refers to an alkyl group as defined above that is substituted with one or more halogen atoms, for example, F, Cl, Br or I.

A “hydroxyl” group refers, in another embodiment, to an OH group. One skilled in the art will recognize that when R1, R2 or R3 in the compounds of the present invention are OR, then R is not OH.

In one embodiment, the term “halogen” or “halo” refers to a halogen such as F, Cl, Br, or I.

In another embodiment, the phrase “phenol” refers to an alcohol (OH) benzene derivative.

In one embodiment of the invention, the present invention relates to the use of a compound described herein and / or its derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or a combination thereof.

In one embodiment of the invention, the methods of the present invention utilize “pharmaceutically acceptable salts” of the compounds, which can be prepared by reacting the compound of the present invention with an acid or base.

Suitable pharmaceutically acceptable salts of the amines of the compounds from an inorganic acid or from an organic acid can be prepared by the methods of the present invention. In one embodiment of the invention, examples of inorganic salts of amines are bisulfates, borates, bromides, chlorides, hemisulphates, hydrobromates, hydrochlorides, 2-hydroxyethylsulfonates (hydroxyethanesulfonates), iodates, iodides, isothionates, nitrates, persulfates, phosphates, sulfates, sulfates, (alkyl sulfonates, aryl sulfonates, halogen-substituted alkyl sulfonates, halogen-substituted aryl sulfonates), sulfonates and thiocyanates.

In one embodiment, examples of organic amine salts may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are acetates, arginines, aspartates, ascorbates, adipates, anthranilates, algenites, alkane carboxylates, alkane carboxylates, alginates, benzenesulfonates, benzoates, bisulfates, butyrates, bicarbonates, bitartrates, carboxylates, citrates, camphorites, camphorsulfonates, cyclohexyl sulfamates, cyclopentane propionates, calcium edetates, camsylates, carbonates, clavulanates, cinnamates, dicarboxylates, digluconates, dodecyl sulfonates, dihydrochlorides, decanoates, enanthates, edonates, edonates, edonates, edonates, edonates, edonates, edonates, edonates, edonates, edonates, edonates, edonates, edonates, edonates, edonates, edonates, edonates, edonates, edonates, edonates, edonates, edonates, edonates, edonates, edonates, edonates, enaterates, , glutamates, glycolates, glucorates, glucoheptanoates, glycerophosphates, gluptates, glycolyllarsanilates, glutarans, glutamates, heptanoates, hexanoates, hydroxy maleate hydroxybenzoates, hydroxy naphthoates, hydrofluoroates, lactates, lactobionates, laurates, malates, maleates, methylenebis (beta-oxynaphthoate), malonates, mandelates, mesylates, methanesulfonates, methyl bromides, methyl nitrates, methyl sulfonates, maleates, nitrates, maleates -naphthalenesulfonates, nicotinates, napsilates, N-methylglucamines, oxalates, octanoates, oleates, pamoates, phenylacetates, picrates, phenylbenzoates, pivalates, propionates, phthalates, pectins, phenylpropionates, palmitates, pantothenates, polygalacturans, pyruvates, quaternites, salicylates, succinates, stearates, sulfanilates, subacetates, tartrates, theophylline acetates, p-toluenesulfonates (tosylates, trifluoroacetates, trifluoroacetates, trifluoroacetates, trisulfonates, terethaloate, tannoate, tannoate, tannoate, tannoate, tannoate, tanoate, tanoate, tanoate, tanno, butyl, .

In one embodiment of the invention, examples of inorganic salts of carboxylic acids or phenols can be selected from ammonium, alkali metals, including lithium, sodium, potassium, cesium; alkaline earth metals include calcium, magnesium, aluminum; zinc, barium, choline, quaternary ammonium.

In another embodiment, examples of organic carboxylic acid salts or phenols may be selected from arginine, organic amines to include aliphatic organic amines, alicyclic organic amines, aromatic organic amines, benzatines, tert-butylamines, benatamines (N-benzylphenethylamine), dicyclohexylamines, dimethylamines, diethanolamines, ethanolamines, ethylenediamines, hydrabamines, imidazoles, lysines, methylamines, melamines, N-methyl-D-glucamine, N, N'-dibenzylethylenediamines, nicotinamides, organic amines, ornithines, pyridines, picols, piperazines, procaine, tris (hydroxymethyl) methylamines, triethylamines, triethanolamines, trimethylamines, tromethamines and ureas.

In one embodiment of the invention, salts can be formed by conventional methods, such as reacting the free basic or free acid forms of the product with one or more equivalents of the corresponding acid or base in a solvent or medium in which the salt is insoluble or in a solvent such as water, which is removed in vacuo or by freeze-drying or by exchanging ions of an existing salt for another ion or suitable ion-exchange resin.

In one embodiment of the invention, the methods of the present invention use a pharmaceutically acceptable salt of the compounds of the present invention. In one embodiment of the invention, the methods of the present invention use a pharmaceutically acceptable salt of the compounds of formulas I-VII. In one embodiment of the invention, the methods of the present invention use an amine salt of the compounds of formulas I-VII of the present invention. In one embodiment of the invention, the methods of the present invention use a phenol salt of the compounds of formulas I-VII of the present invention.

In one embodiment of the invention, the methods of the present invention use a free base, free acid, uncharged or uncomplexed compounds of formulas I-VII and / or its isomer, pharmaceutical product, hydrate, polymorph, or a combination thereof.

In one embodiment of the invention, the methods of the present invention use an isomer of the compound of formulas I-VII. In one embodiment of the invention, the methods of the present invention use a pharmaceutical product of a compound of formulas I-VII. In one embodiment of the invention, the methods of the present invention use a hydrate of the compound of formulas I-VII. In one embodiment, the methods of the present invention use a polymorph of the compound of formula I-VII. In one embodiment of the invention, the methods of the present invention use a metabolite of the compound of formulas I-VII. In another embodiment, the methods of the present invention use a composition comprising a compound of formulas I-VII as described herein, or, in another embodiment, a combination of an isomer, metabolite, pharmaceutical product, hydrate, polymorph of a compound of formula I-VII.

In one embodiment of the invention, the term "isomer" includes, but is not limited to, optical isomers and analogs, structural isomers and analogs, conformational isomers and analogs, and the like.

In one embodiment, the term “isomer” is intended to encompass the optical isomers of a SARD compound. Those skilled in the art will understand that the SARDs of the present invention contain at least one chiral center. Accordingly, SARDs used in the methods of the present invention can exist and be isolated in optically active or racemic forms. Some compounds may also exhibit polymorphism. It should be understood that the present invention encompasses any racemic, optically active, polymorphic, or steroiroisomeric form, or mixtures thereof, which form properties useful for the treatment of androgen-related conditions described herein. In one embodiment of the invention, SARDs are pure (R) isomers. In another embodiment, SARDs are pure (S) -isomers. In another embodiment, the SARDs are a mixture of isomers (R) and (S). In another embodiment, SARDs are a racemic mixture containing an equal amount of (R) and (S) isomers. It is well known in the art how to obtain optically active forms (for example, by resolving the racemic form by recrystallization methods, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).

In another embodiment, the present invention further includes hydrates of the compounds. The invention also includes the use of N-oxides of amino substituents of the compounds described herein.

In one embodiment of the invention, the term "hydrate" refers to hemihydrate, monohydrate, dihydrate, trihydrate, or others, as is known in the art.

The present invention provides, in other embodiments, the use of metabolites of the compounds described herein. In one embodiment of the invention, “metabolite” means any substance derived from another substance through a metabolism or metabolic process.

The compounds described herein can be obtained by any methods known in the art, including, but not limited to, those described in US Patent Application Serial No. 11/505, 363, US Patent Application Serial No. 11 / 505, 499 and US Patent Application Serial No. 11/394, 181; and U.S. Patent Application Serial No. 10/462, 837, which is hereby incorporated by reference in its entirety.

In another example, compounds 13-21, 17a, 49, or 50 are prepared according to Example 1A and Example 1B.

The biological activity of selective androgen degrading receptors

In one embodiment of the invention, the present invention provides a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of prostate cancer (RSA) and its symptoms, or increasing the survival of a male subject suffering from prostate cancer, including administering to the subject a therapeutically effective the amount of the compound or its isomer, a pharmaceutically acceptable salt, a pharmaceutical product, polymorph, hydrate, or any combination thereof represented by a compound of formula I:

I

Where

T represents OH, OR, -NHCOCH3or NHCOR;

Z represents NO2, CN, COOH, COR, NHCOR or CONHR;

Y represents CF3, F, I, Br, Cl, CN, C (R)3 or Sn (R)3;

R represents alkyl, haloalkyl, dihaloalkyl, trialoalkyl, CH2F, chf2CF3CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R1 represents CH3, CH2F, chf2CF3, CH2CH3, or CF2CF3;

R2 represents hydrogen, C1-C12-alkyl, -SO2-aryl, -SO2phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C3-C7cycloalkyl;

where at least two of Q1, Q2, Q3, Q4 and Q5 do not represent hydrogen; or

Q2 and Q3 linked together to form substituted or unsubstituted C5-C8a carbocyclic or heterocyclic ring, and Q1, Q4 and Q5represent, as defined above; and

wherein said carbocyclic or heterocyclic ring formed is not dihydropyridin-2 (1H) -one, pyridin-2 (1H) -one or 1H-pyrrole.

In another embodiment, the prostate cancer is progressive prostate cancer, castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), high-risk nmCRPC, or any combination thereof. In another embodiment, prostate cancer is dependent on AR-FL and / or AR-SV for proliferation. In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the subject has not undergone androgen deprivation therapy (ADT). In another embodiment, the cancer is resistant to treatment with an androgen receptor antagonist. In another embodiment, the cancer is resistant to treatment with enzalutamide, flutamide, bicalutamide, abiraterone, ARN-509, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, spironolactone, or any combination thereof. In another embodiment, administration of a compound to a subject reduces levels of AR, AR-full length (AR-FL), AR-FL with anti-androgen resistance-associated mutations AR-LBD, AR splicing variant (AR-SV), gene-amplified AR or any combination of them in the specified subject.

In one embodiment of the invention, the invention provides a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibition of the progression of prostate cancer (RSA) and its symptoms, or increasing the survival of a male subject with prostate cancer, including administering to the subject a therapeutically effective amount the compound or its isomer, a pharmaceutically acceptable salt, a pharmaceutical product, polymorph, hydrate, or any combination thereof represented by a compound of formula II:

II

Where

T represents OH, OR, -NHCOCH3or NHCOR;

Z represents NO2, CN, COOH, COR, NHCOR or CONHR;

Y represents CF3, F, I, Br, Cl, CN, C (R)3 or Sn (R)3;

R represents alkyl, haloalkyl, dihaloalkyl, trialoalkyl, CH2F, chf2CF3CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R1 represents CH3, CH2F, chf2CF3, CH2CH3, or CF2CF3;

R2 represents hydrogen, C1-C12-alkyl, -SO2-aryl, -SO2phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C3-C7cycloalkyl;

Q3 represents hydrogen, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CF3, CN, NO2, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted arylalkyl, C (R)3, N (R)2NHCOCH3NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3NHCSCF3, NHCSR, NHSO2CH3NHSO2R, OR, COR, OCOR, OSO2R, SO2R, SR, NCS, SCN, NCO, or OCN;

where at least two of Q1, Q2 and Q3 do not represent hydrogen; or

Q1 and Q2 linked together to form substituted or unsubstituted C5-C8a carbocyclic or heterocyclic ring, and Q3 represents, as defined above; or

Q2 and Q3linked together to form substituted or unsubstituted C5-C8a carbocyclic or heterocyclic ring, and Q1 represents, as defined above; and

wherein said carbocyclic or heterocyclic ring formed is not dihydropyridin-2 (1H) -one, pyridin-2 (1H) -one or 1H-pyrrole.

In another embodiment, the prostate cancer is progressive prostate cancer, castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), high-risk nmCRPC, or any combination thereof. In another embodiment, prostate cancer is dependent on AR-FL and / or AR-SV for proliferation. In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the subject has not undergone androgen deprivation therapy (ADT). In another embodiment, the cancer is resistant to treatment with an androgen receptor antagonist. In another embodiment, the cancer is resistant to treatment with enzalutamide, flutamide, bicalutamide, abiraterone, ARN-509, AZD-3514, galeronone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, spironolactone, or any combination thereof. In another embodiment, administering a compound to a subject reduces levels of AR, AR-full length (AR-FL), AR-FL with anti-androgen resistance-associated mutations AR-LBD, AR splicing variant (AR-SV), gene-amplified AR or any combination thereof to said subject.

III

Where

Z represents NO2 or CN;

Y represents CF3F, I, Br, Cl, or CN;

R2 represents hydrogen, C1-C12-alkyl, -SO2-aryl, -SO2phenyl, -CO-aryl, arylalkyl, benzyl, aryl, or C3-C7cycloalkyl

Q1 represents substituted or unsubstituted aryl, substituted or unsubstituted phenyl, substituted or unsubstituted arylalkyl, CN or NO2;

Q2 represents hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CF3, CN, NO2, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted arylalkyl;

where at least one of Q2 and Q3 represents substituted or unsubstituted aryl, substituted or unsubstituted phenyl, or substituted or unsubstituted arylalkyl; or

Q2 and Q3 linked together to form substituted or unsubstituted C5-C8 carbocyclic or heterocyclic rings, and Q1 represents, as defined above.

In another embodiment, the prostate cancer is progressive prostate cancer, castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), high-risk nmCRPC, or any combination thereof. In another embodiment, prostate cancer is dependent on AR-FL and / or AR-SV for proliferation. In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the subject has not undergone androgen deprivation therapy (ADT). In another embodiment, the cancer is resistant to treatment with an androgen receptor antagonist. In another embodiment, the cancer is resistant to treatment with enzalutamide, flutamide, bicalutamide, abiraterone, ARN-509, AZD-3514, galeronone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, spironolactone, or any combination thereof. In another embodiment, administering a compound to a subject reduces levels of AR, AR-full length (AR-FL), AR-FL with anti-androgen resistance-associated mutations AR-LBD, AR splicing variant (AR-SV), gene-amplified AR or any combination thereof to said subject.

III

Where

Z represents NO2 or CN;

Y represents CF3F, I, Br, Cl, or CN;

where at least one of Q1, Q2 and Q3 is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted phenyl;

Q1 and Q2linked together to form substituted or unsubstituted C5-C8a carbocyclic or heterocyclic ring, and Q3 represents, as defined above;

Q2 and Q3linked together to form substituted or unsubstituted C5-C8 carbocyclic or heterocyclic rings, and Q1 represents, as defined above; and

wherein said carbocyclic or heterocyclic ring formed is not dihydropyridin-2 (1H) -one, pyridin-2 (1H) -one or 1H-pyrrole.

In another embodiment, the prostate cancer is progressive prostate cancer, castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), high-risk nmCRPC, or any combination thereof. In another embodiment, prostate cancer is dependent on AR-FL and / or AR-SV for proliferation. In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the subject has not undergone androgen deprivation therapy (ADT). In another embodiment, the cancer is resistant to treatment with an androgen receptor antagonist. In another embodiment, the cancer is resistant to treatment with enzalutamide, flutamide, bicalutamide, abiraterone, ARN-509, AZD-3514, galeronone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, spironolactone, or any combination thereof. In another embodiment, administering a compound to a subject reduces levels of AR, AR-full length (AR-FL), AR-FL with anti-androgen resistance-associated mutations AR-LBD, AR splicing variant (AR-SV), gene-amplified AR or any combination thereof to said subject.

IV

Where

T represents OH, OR, -NHCOCH3or NHCOR;

Z represents NO2, CN, COOH, COR, NHCOR or CONHR;

Y represents CF3, F, I, Br, Cl, CN, C (R)3 or Sn (R)3;

R represents alkyl, haloalkyl, dihaloalkyl, trialoalkyl, CH2F, chf2CF3CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R1 represents CH3, CH2F, chf2CF3, CH2CH3, or CF2CF3;

Q1 and Q2 linked together to form substituted or unsubstituted C5-C8 carbocyclic or heterocyclic rings.

In another embodiment, the prostate cancer is progressive prostate cancer, castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), high-risk nmCRPC, or any combination thereof. In another embodiment, prostate cancer is dependent on AR-FL and / or AR-SV for proliferation. In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the subject has not undergone androgen deprivation therapy (ADT). In another embodiment, the cancer is resistant to treatment with an androgen receptor antagonist. In another embodiment, the cancer is resistant to treatment with enzalutamide, flutamide, bicalutamide, abiraterone, ARN-509, AZD-3514, galeronone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, spironolactone, or any combination thereof. In another embodiment, administering a compound to a subject reduces levels of AR, AR-full length (AR-FL), AR-FL with anti-androgen resistance-associated mutations AR-LBD, AR splicing variant (AR-SV), gene-amplified AR or any combination thereof to said subject.

V

Where

T represents OH, OR, -NHCOCH3or NHCOR;

Z represents NO2, CN, COOH, COR, NHCOR or CONHR;

Y represents CF3, F, I, Br, Cl, CN, C (R)3 or Sn (R)3;

R represents alkyl, haloalkyl, dihaloalkyl, trialoalkyl, CH2F, chf2CF3CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R1 represents CH3, CH2F, chf2CF3, CH2CH3, or CF2CF3; and

In another embodiment, the prostate cancer is progressive prostate cancer, castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), high-risk nmCRPC, or any combination thereof. In another embodiment, prostate cancer is dependent on AR-FL and / or AR-SV for proliferation. In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the subject has not undergone androgen deprivation therapy (ADT). In another embodiment, the cancer is resistant to treatment with an androgen receptor antagonist. In another embodiment, the cancer is resistant to treatment with enzalutamide, flutamide, bicalutamide, abiraterone, ARN-509, AZD-3514, galeronone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, spironolactone, or any combination thereof. In another embodiment, administering a compound to a subject reduces levels of AR, AR-full length (AR-FL), AR-FL with anti-androgen resistance-associated mutations AR-LBD, AR splicing variant (AR-SV), gene-amplified AR or any combination thereof to said subject.

VI

Where

T represents OH, OR, -NHCOCH3or NHCOR;

Z represents NO2, CN, COOH, COR, NHCOR or CONHR;

Y represents CF3, F, I, Br, Cl, CN, C (R)3 or Sn (R)3;

R represents alkyl, haloalkyl, dihaloalkyl, trialoalkyl, CH2F, chf2CF3CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R1 represents CH3, CH2F, chf2CF3, CH2CH3, or CF2CF3;

Q1 and Q2 linked together to form substituted or unsubstituted C5-C8a carbocyclic or heterocyclic ring.

In another embodiment, the prostate cancer is progressive prostate cancer, castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), high-risk nmCRPC, or any combination thereof. In another embodiment, prostate cancer is dependent on AR-FL and / or AR-SV for proliferation. In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the subject has not undergone androgen deprivation therapy (ADT). In another embodiment, the cancer is resistant to treatment with an androgen receptor antagonist. In another embodiment, the cancer is resistant to treatment with enzalutamide, flutamide, bicalutamide, abiraterone, ARN-509, AZD-3514, galeronone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, spironolactone, or any combination thereof. In another embodiment, administering a compound to a subject reduces levels of AR, AR-full length (AR-FL), AR-FL with anti-androgen resistance-associated mutations AR-LBD, AR splicing variant (AR-SV), gene-amplified AR or any combination thereof to said subject.

VII

Where

T represents OH, OR, -NHCOCH3or NHCOR;

Z represents NO2, CN, COOH, COR, NHCOR or CONHR;

Y represents CF3, F, I, Br, Cl, CN, C (R)3 or Sn (R)3;

R represents alkyl, haloalkyl, dihaloalkyl, trialoalkyl, CH2F, chf2CF3CF2CF3, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

R1 represents CH3, CH2F, chf2CF3, CH2CH3, or CF2CF3; and

In another embodiment, the prostate cancer is progressive prostate cancer, castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), high-risk nmCRPC, or any combination thereof. In another embodiment, prostate cancer is dependent on AR-FL and / or AR-SV for proliferation. In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the subject has not undergone androgen deprivation therapy (ADT). In another embodiment, the cancer is resistant to treatment with an androgen receptor antagonist. In another embodiment, the cancer is resistant to treatment with enzalutamide, flutamide, bicalutamide, abiraterone, ARN-509, AZD-3514, galeronone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, spironolactone, or any combination thereof. In another embodiment, administering a compound to a subject reduces levels of AR, AR-full length (AR-FL), AR-FL with anti-androgen resistance-associated mutations AR-LBD, AR splicing variant (AR-SV), gene-amplified AR or any combination thereof to said subject.

In another embodiment, the prostate cancer is progressive prostate cancer, castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), high-risk nmCRPC, or any combination thereof. In another embodiment, prostate cancer is dependent on AR-FL and / or AR-SV for proliferation. In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the subject has not undergone androgen deprivation therapy (ADT). In another embodiment, the cancer is resistant to treatment with an androgen receptor antagonist. In another embodiment, the cancer is resistant to treatment with enzalutamide, flutamide, bicalutamide, abiraterone, ARN-509, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, keto conazole, spironolactone, or any combination thereof. In another embodiment, administering a compound to a subject reduces levels of AR, AR-full length (AR-FL), AR-FL with anti-androgen resistance-associated mutations AR-LBD, AR splicing variant (AR-SV), gene-amplified AR or any combination thereof to said subject.

In one embodiment of the invention, the methods of the present invention are directed to treating, suppressing, reducing the incidence of a disease, reducing severity, inhibiting, providing palliative care, or increasing the survival of a subject suffering from prostate cancer. In one embodiment of the invention, the methods of the present invention are directed to treating, suppressing, reducing the incidence of a disease, reducing severity, inhibiting, providing palliative care, or increasing the survival of a subject suffering from progressive prostate cancer. In one embodiment, the methods of the present invention are directed to treating, suppressing, reducing the incidence of a disease, reducing severity, inhibiting, providing palliative care, or increasing the survival of a subject suffering from castration-resistant prostate cancer (CRPC). In one embodiment of the invention, the methods of the present invention are directed to treating, suppressing, reducing the incidence of a disease, reducing severity, inhibiting, providing palliative care, or increasing the survival of a subject suffering from metastatic castration-resistant prostate cancer (mCRPC). In one embodiment, the methods of the present invention are directed to treating, suppressing, reducing the incidence of a disease, reducing severity, inhibiting, providing palliative care, or increasing the survival of a subject suffering from non-metastatic castration-resistant prostate cancer (nmCRPC). In one embodiment, nmCRPC is a high-risk nmCRPC. In another embodiment, the subject has a high or elevated level of prostate antigen (PSA).

In one embodiment of the invention, the invention provides a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibition of the progression of prostate cancer (RSA) and its symptoms, or increasing the survival of a male subject suffering from prostate cancer, including administering to the subject a therapeutically effective the amount of the SARD compound or isomer thereof, a pharmaceutically acceptable salt, a pharmaceutical product, polymorph, hydrate, or any combination thereof, said compound is represented by a compound of formulas I-VII or any of compounds 13-21, 49, 50 and 17a.

In one embodiment of the invention, the invention provides a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the development of progressive prostate cancer and its symptoms, or increasing the survival of a male subject suffering from progressive prostate cancer, including administering to the subject a therapeutically effective amount compounds of SARD or its isomer, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof, said compound is represented by a compound of formulas I-VII or any of compounds 13-21, 49, 50 and 17a.

In one embodiment, the invention provides a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibition of the progression of metastatic prostate cancer and its symptoms, or increasing the survival of a male subject suffering from metastatic prostate cancer, including administering to the subject a therapeutically effective amount compounds of SARD or its isomer, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof, said compound is represented by a compound of formulas I-VII or any of compounds 13-21, 49, 50 and 17a.

In one embodiment, the invention provides a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of castration-resistant prostate cancer (CRPC) and its symptoms, or increasing the survival of a male subject suffering from castration-resistant prostate cancer ( CRPC) including administering to a specified subject a therapeutically effective amount of a SARD compound or isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof, said compound is represented by a compound of formulas I-VII or any of compounds 13-21, 49, 50 and 17a.

In one embodiment of the invention, SARD compounds, as described herein, and / or compositions containing them, can be used to treat, suppress, reduce the incidence of the disease, reduce the severity or inhibit the progression of castration-resistant prostate cancer (CRPC) and its symptoms, or increased survival of men with castration-resistant prostate cancer. In another embodiment, the CRPC is a metastatic CRPC (mCRPC). In another embodiment, the CRPC is a metastatic CRPC (nmCRPC). In one embodiment, nmCRPC is a high-risk nmCRPC. In another embodiment, the subject further receives androgen deprivation therapy.

As used herein, the terms “increase” and “extension” can be used interchangeably having all the same meanings and qualities, and these terms may, in one embodiment, refer to lengthening time. In another embodiment of the invention, as used here, the terms “magnification”, “enlarging”, “enlarged”, can be used interchangeably and refer to an object that is becoming more significant (both in size, quantity, number or intensity), where, for example , the object is a sex hormone-binding globulin (SHBG) or a specific antigen of the prostate gland (PSA).

In one embodiment of the invention, the compounds and / or compositions containing them described herein can be used to increase metastasis-free survival (MFS) in a subject suffering from non-metastatic prostate cancer. In one embodiment, non-metastatic prostate cancer is a non-metastatic progressive prostate cancer. In one embodiment, non-metastatic prostate cancer is non-metastatic CRPC (nmCRPC). In one embodiment, nmCRPC is a high-risk nmCRPC.

In one embodiment of the invention, SARD compounds, as described herein, and / or compositions containing them, can be used to provide dual effects, for example, in the treatment of prostate cancer and the prevention of metastases. In one embodiment of the invention, the prostate cancer being treated is a progressive prostate cancer. In one embodiment, the prostate cancer to be treated is castration-resistant prostate cancer (CRPC). In one embodiment of the invention, the prostate cancer being treated is a metastatic CRPC (mCRPC). In one embodiment of the invention, the prostate cancer being treated is a non-metastatic CRPC (nmCRPC). In one embodiment, nmCRPC is a high-risk nmCRPC.

Men with progressive prostate cancer who are at a high risk of progression to castration-resistant prostate cancer (CRPC), In one embodiment of the invention, men with ADT with a total serum testosterone concentration of more than 20 ng / dl or in another embodiment of the invention, men with progressive prostate cancer, which at the time of the onset of ADT had either (1) a confirmed Gleason pattern of stage 4 or 5 prostate cancer, (2) metastatic prostate cancer, (3) PSA doubling time <3 months, (4) PSA≥20 ng / ml, or (5) relapse of PSA within <3 years after final local therapy (radical prostatectomy or radiation therapy).

Men with high-risk non-metastatic castration-resistant prostate cancer (high-risk nmCRPC) may include those with fast PSA doubling times, with an expected survival without progression of about 18 months or less (MillerK, MoulJW, GleaveM, et al. 2013. Phase III, randomized, placebo-controlled study of once-daily oral zibotentan (ZD4054) in patients with non-metastatic castration-resistant prostate cancer. ProstateCancProstDis. Feb; 16: 187-192). This relatively rapid progression of their disease underlines the importance of new treatments for these individuals. In one embodiment of the invention, PSA levels are above 8 ng / ml in a subject suffering from high-risk nmCRPC. In one embodiment, the PSA doubling time is less than 8 months in a subject suffering from high-risk nmCRPC. In another embodiment, the PSA doubling time is less than 10 months in a subject suffering from high-risk nmCRPC. In one embodiment, the total serum testosterone level is above 20 ng / ml in a subject suffering from high-risk nmCRPC. In one embodiment of the invention, serum free testosterone levels are greater than those observed in an ochridodectomized male subject suffering from high-risk nmCRPC.

In one embodiment of the invention, the compounds and / or compositions containing them described herein can be used in combination with an LHRH agonist or antagonist to increase the progression-free or overall survival of a patient suffering from prostate cancer. In another embodiment, the prostate cancer is a progressive prostate cancer. In another embodiment, prostate cancer is a castration-resistant prostate cancer (CRPC). In another embodiment, the CRPC is a metastatic CRPC (mCRPC). In another embodiment, the CRPC is a non-metastatic CRPC (nmCRPC). In one embodiment, nmCRPC is a high-risk nmCRPC. In another embodiment, the subject is surgically castrated. In another embodiment, the subject is chemically castrated.

In one embodiment of the invention, the compounds and / or compositions comprising them described herein can be used in combination with anti-programmable death receptor 1 (anti-PD-1) drugs (e.g., AMP-224, nivolumab, pembrolizumab, pidilizumab, AMP-554 and the like) to increase the progression-free or overall survival of a patient suffering from prostate cancer. In another embodiment, the prostate cancer is a progressive prostate cancer. In another embodiment, prostate cancer is a castration-resistant prostate cancer (CRPC). In another embodiment, the CRPC is a metastatic CRPC (mCRPC). In another embodiment, the CRPC is a non-metastatic CRPC (nmCRPC). In one embodiment, nmCRPC is a high-risk nmCRPC. In another embodiment, the subject is surgically castrated. In another embodiment, the subject is chemically castrated.

In one embodiment of the invention, the compounds and / or compositions containing them described herein can be used in combination with anti-PD-L1 drugs (e.g., BMS-936559, MEDI4736, MPDL3280A, MEDI4736, MSB0010718C, etc.) to increase survival without progression or overall survival of a subject suffering from prostate cancer. In another embodiment, the prostate cancer is a progressive prostate cancer. In another embodiment, prostate cancer is a castration-resistant prostate cancer (CRPC). In another embodiment, the CRPC is a metastatic CRPC (mCRPC). In another embodiment, the CRPC is a non-metastatic CRPC (nmCRPC). In one embodiment, nmCRPC is a high-risk nmCRPC. In another embodiment, the subject is surgically castrated. In another embodiment, the subject is chemically castrated.

In some embodiments of the invention, the treatment of prostate cancer, advanced prostate cancer, CRPC, mCRPC and / or nmCRPC can lead to clinically significant improvement in the symptoms, functions and / or survival associated with prostate cancer. Clinically significant improvements include, but are not limited to, an increase in cancer progression-free survival (rPFS) if the cancer is metastatic, and an increase in metastasis-free survival (MFS) if the cancer is non-metastatic.

In one embodiment of the invention, the compounds as described herein and / or compositions containing them can be used to increase the survival of men with castration-resistant prostate cancer (CRPC). In another embodiment, the CRPC is a metastatic CRPC (mCRPC). In another embodiment, the CRPC is a non-metastatic CRPC (nmCRPC). In one embodiment, nmCRPC is a high-risk nmCRPC. In another embodiment, the subject further receives androgen deprivation therapy.

In one embodiment, prostate specific antigen (PSA) levels that are considered normal are age dependent. In one embodiment, the levels of specific prostate antigen (PSA) that are considered normal depend on the size of the male prostate gland. In one embodiment of the invention, PSA levels in the range of 2.5 to 10 ng / ml are considered “boundary”. In another embodiment, PSA levels above 10 ng / ml are considered “high”.

In one embodiment, the rate of change or “growth rate of PSA content” is high. In one embodiment of the invention, the rate of change or “rate of increase in PSA content” in excess of 0.75 / year is considered high.

In one embodiment, the invention provides a method for reducing serum specific prostate antigen (PSA) levels in a male subject suffering from prostate cancer, progressive prostate cancer, metastatic prostate cancer, or castration-resistant prostate cancer (CRPC), comprising administering a therapeutically effective amount of a SARD compound or isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof, the compound is represented by the structure of formula I-VII or any of compounds 13-21, 49, 50 and 17a.

In one embodiment of the invention, the invention is directed to the treatment of a subject with high or elevated levels of PSA, comprising administering the SARD compound of the present invention. In one embodiment, the invention is directed to treating a subject with a high or elevated PSA level despite persistent ADT or a history of ADT, surgical castration, or despite treatment with antiandrogens and / or an LHRH agonist. In another embodiment, the compounds of formula I-VII or any of compounds 13-21, 49, 50 and 17a are used for treatment.

In one embodiment of the invention, the invention provides a method for treating, suppressing, reducing the incidence of diseases, reducing the severity or inhibiting the progression of castration-resistant prostate cancer (CRPC) and its symptoms, or increasing the survival of men with castration-resistant prostate cancer, including administering a therapeutically effective amount of a compound of formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof. In another embodiment, the compound is compound 13. In another embodiment, the compound is compound 14. In another embodiment, the compound is compound 15. In another embodiment, the compound is compound 16. In another embodiment, the compound is compound 17. In another embodiment, the compound is compound 17a. In another embodiment, the compound is compound 18. In another embodiment, the compound is compound 19. In another embodiment, the compound is compound 20. In another embodiment, the compound is compound 21. In another embodiment, the compound is compound 49. In another embodiment, the compound is compound 50.

In one embodiment, the invention provides a secondary hormone therapy method that reduces serum PSA in a male subject suffering from castration-resistant prostate cancer (CRPC), comprising administering a therapeutically effective amount of a compound of Formulas I-VII or an isomer thereof a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof. In another embodiment, castration is surgical castration. In another embodiment, subject to the methods described above, prostate cancer is dependent on AR-FL and / or AR-SV for proliferation. In another embodiment, the cancer is resistant to treatment with an androgen receptor antagonist. In another embodiment, the cancer is resistant to treatment with enzalutamide, flutamide, bicalutamide, abiraterone, ARN-509, AZD-3514, galeronone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, spironolactone, or any combination thereof. In another embodiment, the administration of compounds of formulas I-VII reduces the levels of AR, AR full length (AR-FL), AR-FL with antiandrogen resistance, associating AR-LBD mutations, AR splicing variant (AR-SV), amplified gene AR or any combination thereof to a subject. In another embodiment, castration is surgical castration. In another embodiment of the invention, castration is chemical castration. In another embodiment, the CRPC is a metastatic CRPC (mCRPC). In another embodiment, the CRPC is a non-metastatic CRPC (nmCRPC). In one embodiment, nmCRPC is a high-risk nmCRPC. In another embodiment of the invention, the method further enhances survival without radiographic progression (rPFS) in a subject suffering from metastatic cancer. In another embodiment of the invention, the method further increases metastasis-free survival (MFS) in a subject suffering from non-metastatic cancer. In one embodiment of the invention, the method can be used to provide a dual action, for example, the treatment of prostate cancer and the prevention of metastases. In another embodiment, the subject has not undergone androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the subject further receives an LHRH agonist or antagonist. In another embodiment, the LHRH agonist is leuprolide acetate. In another embodiment, the subject underwent an orchidectomy. In another embodiment, the subject has a high or elevated level of specific prostate antigen (PSA). In another embodiment, the subject is a patient with prostate cancer. In another embodiment, the subject is a patient with prostate cancer on ADT. In another embodiment, the subject is a patient with prostate cancer on ADT with castration levels of total T. In another embodiment, the subject is a patient with advanced prostate cancer. In another embodiment, the subject is a patient with advanced prostate cancer on ADT. In another embodiment, the subject is a patient with advanced prostate cancer on ADT with castration levels of total T. In another embodiment, the subject is a CRPC of a patient. In another embodiment, the subject is a patient CRPC on ADT. In another embodiment, the subject is a CRPC of a patient on ADT with castration levels of total T. In another embodiment, the subject is a patient with metastatic castration-resistant prostate cancer (mCRPC). In another embodiment, the subject is a patient mCRPC supported by ADT. In another embodiment, the subject is a patient mCRPC supported by ADT with castration levels of total T. In another embodiment, the subject is a patient with non-metastatic castration-resistant prostate cancer (nmCRPC). In another embodiment, the subject is a patient nmCRPC supported by ADT. In another embodiment, the subject is a patient’s nmCRPC supported by ADT with castration levels of total T. In another embodiment, nmCRPC is a high-risk nmCRPC. In another embodiment, the method further treats, suppresses, reduces the incidence of morbidity, reduces the severity, or inhibits progressive prostate cancer. In another embodiment, the method further provides palliative treatment for advanced prostate cancer.

In one embodiment of the invention, the present invention is directed to a method of reducing levels of AR, AR full length, AR-FL with antiandrogen resistance, associating AR-LBD mutations and / or AR splicing variants in a subject, comprising administering to the subject a therapeutically effective amount of a SARD compound in in accordance with the present invention or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof. In another embodiment, the reduction is achieved by degradation of said AR, AR-full length (AR-FL) and / or AR-splicing variants (AR-SV). In another embodiment, the reduction is achieved by inhibiting said AR, AR-full length (AR-FL) and / or AR-splicing variants (AR-SV). In another embodiment, the reduction is achieved due to the double degradation of AR-SV / AR-FL and the inhibitory functions of AR-SV / AR-FL.

In one embodiment of the invention, the invention is directed to a method of reducing the levels of AR splicing variants in a subject, comprising administering to the subject a therapeutically effective amount of a SARD compound of the present invention or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any one thereof combinations. In another embodiment of the invention, the method further reduces AR-full length (AR-FL) levels in a subject. In another embodiment, the reduction is achieved due to the degradation of these AR splicing variants (AR-SV). In another embodiment, the reduction is further achieved by degradation of said AR-FL. In another embodiment, the reduction is achieved by inhibiting said AR splicing (AR-SV) variants. In another embodiment, the reduction is further achieved by inhibiting said AR-FL. In another embodiment, the reduction is achieved due to the double degradation of AR-SV and the inhibitory functions of AR-SV. In another embodiment, the reduction is achieved due to the double degradation of AR-FL and the inhibitory functions of AR-FL.

In one embodiment, a “subject suffering from castration-resistant prostate cancer” refers to a subject who has previously been treated with androgen deprivation therapy (ADT), has responded to ADT, and currently has a plasma PSA level> 2 ng / ml or> 2 ng / ml and which is about 25% more than the lowest level achieved on ADT. In another embodiment, the term refers to a subject who, despite maintaining androgen deprivation therapy, is diagnosed with progression of serum PSA. In another embodiment, the subject has a castration level of total serum testosterone (<50 ng / dl). In another embodiment, the subject has a castration level of total serum testosterone (<20 ng / dl). In another embodiment, the subject has an elevated serum PSA level on two consecutive evaluations for at least 2 weeks. In another embodiment, the subject has been effectively treated with ADT. In another embodiment, the subject has a serum PSA response history after the onset of ADT. In another embodiment, the subject was treated with ADT and had an initial serum PSA response, but now has a serum PSA level> 2 ng / ml and an increase of about 25% than the lowest level observed on ADT. In one embodiment, the CRPC is a metastatic CRPC (mCRPC). In another embodiment, the CRPC is a non-metastatic CRPC (nmCRPC). In one embodiment, nmCRPC is a high-risk nmCRPC.

The term “serum PSA response” refers, in one embodiment, to a decrease in serum PSA levels of at least 90% before initiation of ADT to <10 ng / ml or an undetectable serum PSA level (<0, 2 ng / ml) at any time or in another embodiment of the invention is reduced by at least 50% from the initial level of serum PSA, or in another embodiment is reduced by at least 90% from the initial level of serum PSA, or in another embodiment, at least 30% decrease from the initial level of serum PSA, or in another embodiment, at least a 10% decrease from the initial level of serum PSA.

The term “progression of serum PSA” refers in one embodiment to an increase in serum implementation of the invention by 25% or more and an absolute increase of 2 ng / ml or more from the lowest level or in another embodiment, serum PSA> 2 ng / ml or> 2 ng / ml and 25% higher than the lowest level after initiation of androgen deprivation therapy (ADT).

In another embodiment, the term “lowest level” refers to the lowest level of PSA when a patient undergoes ADT.

Testosterone can be measured as “free” (that is, bioavailable and unbound) or as “total” (including the percentage that is protein bound and inaccessible) serum levels. In one embodiment, total serum testosterone contains free testosterone and associated testosterone.

The methods of this invention include administering a combination of forms of ADT and a compound of the present invention. In one embodiment, the forms of ADT include an LHRH agonist. In another embodiment, the LHRH agonist comprises leuprolide acetate (Lupron®) (US 5, 480, 656; US 5, 575, 987; 5, 631, 020; 5, 643, 607; 5, 716, 640; 5, 814 , 342; 6, 036, 976, which are incorporated herein by reference) or goserelin acetate (Zoladex®) (US 7, 118, 552; 7, 220, 247; 7, 500, 964, which are incorporated into this description by links). In one embodiment, the forms of ADT include an LHRH antagonist. In another embodiment, the LHRH antagonist comprises degarelix. In another embodiment, the forms of ADT include reversible antiandrogens. In another embodiment, antiandrogens include bicalutamide, flutamide, finasteride, dutasteride, enzalutamide, nilutamide, chlormadinone, an abirator, or any combination thereof. In one embodiment, forms of ADT include bilateral orchidectomy.

In one embodiment of the invention, the invention provides a method of treating, suppressing, reducing the incidence of diseases, reducing the severity or inhibiting the progression of castration-resistant prostate cancer (CRPC) and its symptoms, or increasing the survival of men with castration-resistant prostate cancer, comprising administering a therapeutically effective amount of a combination of one or more forms of ADT and a compound of formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof. In another embodiment, the subject has not undergone androgen deprivation therapy (ADT).

In one embodiment, the invention provides a method for reducing serum PSA levels in a male suffering from castration-resistant prostate cancer (CRPC), comprising administering a therapeutically effective amount of a combination of one or more forms of ADT and a compound of formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof. In another embodiment, the subject has not undergone androgen deprivation therapy (ADT).

In one embodiment, the methods of the present invention comprise administering a therapeutically effective amount of an antiandrogen and a compound of the present invention. In one embodiment, the methods of the present invention comprise administering a therapeutically effective amount of an LHRH agonist and a compound of the present invention. In one embodiment, the methods of the present invention comprise administering a therapeutically effective amount of an antiandrogen, an LHRH agonist, and a compound of the present invention. In another embodiment, the compound is a compound of formulas I-VII. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment, the methods of the present invention comprise administering a therapeutically effective amount of a lyase inhibitor (eg, abirator) and a compound of the present invention. In another embodiment, the compound is a compound of formulas I-VII. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In another embodiment, the invention provides a method for treating androgen deprivation (ADT) in a subject, comprising administering a therapeutically effective amount of a compound of Formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof. In another embodiment, the subject has prostate cancer. In another embodiment, prostate cancer is a castration-resistant prostate cancer (CRPC). In another embodiment, the CRPC is a metastatic CRPC (mCRPC). In one embodiment, the CRPC is metastatic castration-resistant prostate cancer (nmCRPC). In one embodiment, nmCRPC is a high-risk nmCRPC. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a. In another embodiment, the subject has not undergone androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT).

In one embodiment, the invention provides a method for treating prostate cancer or slowing the progression of prostate cancer, comprising administering a SARD compound of the present invention. In one embodiment of the invention, the invention provides a method for the prevention and / or treatment of recurrence of prostate cancer, comprising the SARD compounds of the present invention. In another embodiment, prostate cancer is a castration-resistant prostate cancer (CRPC). In another embodiment, the CRPC is a metastatic CRPC (mCRPC). In one embodiment, the CRPC is non-metastatic castration-resistant prostate cancer (nmCRPC). In one embodiment, nmCRPC is a high-risk nmCRPC.

In one embodiment, the invention provides a method for increasing the survival of a subject having prostate cancer, progressive prostate cancer, castration-resistant prostate cancer, or metastatic castration-resistant prostate cancer or non-metastatic castration-resistant prostate cancer, or highly sensitive non-metastatic castration-resistant resistant prostate cancer comprising administering a compound of the present invention. In another embodiment, administering a compound of the present invention in combination with LHRH analogues, reversible antiandrogens (such as bicalutamide, flutamide or enzalutamide), antiestrogens, estrogens (such as estradiol, ethinyl estradiol or capesar), anti-cancer drugs, 5-alpha inhibitors reductases, aromatase inhibitors, progestins, selective androgen receptor modulators (SARMs), or agents acting through other nuclear hormone receptors. In another embodiment, the subject has not undergone androgen deprivation therapy (ADT). In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

The term "progressive prostate cancer" refers to metastatic cancer originating in the prostate gland and widely metastasizing outside the prostate gland, for example, surrounding tissues, including the seminal glands, pelvic lymph nodes or bones, or other parts of the body. The pathology of prostate cancer is evaluated with a Gleason score of 1 to 5 in order of increasing malignancy. In another embodiment, patients with a significant risk of disease progression and / or death from prostate cancer should be included in the definition and that any patient with cancer outside the capsule of the prostate with disease stages lower than IIB clearly has a “progressive” disease. In another embodiment, “progressive prostate cancer” may refer to locally advanced prostate cancer.

Men with advanced prostate cancer often receive treatment to block the production of androgens, which are male sex hormones that can contribute to the growth of prostate tumors. However, prostate cancer, which initially responds to antiandrogen therapy, ultimately develops the ability to grow without androgens. Such cancers are often referred to as hormonal refractory, androgen-independent, or castration-resistant.

In one embodiment of the invention, progressive prostate cancer is a castration-resistant prostate cancer.

The term "castration-resistant prostate cancer" (CRPC) refers to progressive prostate cancer that worsens or progresses while the patient remains on ADT or other treatments to lower testosterone or prostate cancer, which is considered hormonal refractory without prior hormone therapy, androgen-independent either chemically or surgically castration-resistant. In another embodiment, the CRPC is the result of activation of AR by intracrine synthesis of androgens. In another embodiment, CRPC is the result of the expression of AR splicing variants (AR-SV) that lack a ligand binding domain (LBD). In another embodiment, the CRPC is the result of the expression of AR-LBD mutations that are able to withstand antagonists. In another embodiment, castration-resistant prostate cancer (CRPC) is a progressive prostate cancer that has developed despite ongoing ADT and / or surgical castration. In one embodiment, castration-resistant prostate cancer is defined as prostate cancer that continues to progress or worsens or adversely affects a patient’s health despite prior surgical castration, ongoing treatment with gonadotropin-releasing hormone agonists (e.g., leuprolide) or antagonists ( e.g. degarelix), antiandrogens (e.g. bicalutamide, flutamide, enzalutamide, ketoconazole, aminoglutamide), chemotherapeutic agents (for example, docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors (imatinib (Gleevec®) or gefitinib (Iressa®), cabosantinib 4, or Comet other treatments for prostate cancer (e.g. vaccines (Sipuleul-T (Provenge®), GVAX, etc.), herbal (PC-SPES), and lyase inhibitors (abiraterone)), as evidenced by an increase or higher levels of serum prostate antigen (PSA), metastases, bone metastases, pain, involvement of lymph nodes, an increase in the size or markers of serum for tumor growth, deterioration in diagnostic prognostic markers, or patient condition.

In one embodiment of the invention, castration-resistant prostate cancer is defined as not having previous hormone therapy for prostate cancer.

Many early prostate cancers require androgens for growth, but progressive prostate cancers in some embodiments of the invention are androgen-independent or without prior hormone therapy. In one embodiment of the invention, in men with castration-resistant prostate cancer, the tumor cells may be able to grow in the absence of androgens (hormones that promote the development and maintenance of male sexual characteristics).

In one embodiment of the invention, the term “androgen deprivation therapy” (ADT) or “traditional androgen deprivation therapy” is directed to orchidectomy (surgical castration) in which the surgeon removes the testes. In another embodiment, the term “androgen deprivation therapy” or “conventional androgen deprivation therapy” is directed to the administration of luteinizing hormone-releasing hormone (LHRH) analogues: these drugs reduce the amount of testosterone produced by the testes. Examples of LHRH analogues available in the United States are leuprolide (Lupron®, Viadur®, Eligard®), goserelin (Zoladex®), triptorelin (Trelstar®) and histrelin (Vantas®). In another embodiment, the term “androgen deprivation therapy” or “conventional androgen deprivation therapy” is directed to the administration of antiandrogens: antiandrogens block the body’s ability to use any androgens. Even after orchidectomy or during treatment with LHRH analogues, a small amount of androgen is still produced by the adrenal glands. Examples of antiandrogenic drugs include enzalutamide (Xtandi®), flutamide (Eulexin®), bicalutamide (Casodex®) and nilutamide (Nilandron®). In another embodiment, the term “androgen deprivation therapy” or “conventional androgen deprivation therapy” is directed to the administration of luteinizing hormone-releasing hormone (LHRH) antagonists such as abarelix (Plenaxis®) or degarelix (Firmagon®) (approved for use by the FDA in 2008 for the treatment of advanced prostate cancer). In another embodiment, the term “androgen deprivation therapy” or “traditional androgen deprivation therapy” is directed to the administration of 5α-reductase inhibitors such as finasteride (Proscar®) and dutasteride (Avodart®): 5α-reductase inhibitors block the body’s ability to convert testosterone to more active androgen, 5α-dihydrotestosterone (DHT). In another embodiment, the term “androgen deprivation therapy” or “conventional androgen deprivation therapy” is directed to the administration of testosterone biosynthesis inhibitors such as ketoconazole (Nizoral®). In another embodiment, the term “androgen deprivation therapy” or “conventional androgen deprivation therapy” is directed to the administration of estrogens such as diethylstilbestrol, ethinyl estradiol, capesaris or 17β-estradiol. In another embodiment, the term “androgen deprivation therapy” or “conventional androgen deprivation therapy” is directed to the administration of 17α-hydroxylase / C17, 20 lyase inhibitors (CYP17A1), such as an abirator (Zytiga®).

In one embodiment of the invention, the invention provides a method for treating, suppressing, reducing the incidence of diseases, reducing severity, increasing survival or inhibiting antiandrogen-resistant prostate cancer. In another embodiment, the antiandrogen is bicalutamide, hydroxyflutamide, flutamide, or enzalutamide.

In one embodiment of the invention, the invention provides a method of treating, suppressing, reducing the incidence of diseases, reducing severity, increasing survival or inhibiting resistance to prostate cancer abaraterone.

Muscle Atrophy (MA) is characterized by a loss or contraction of muscle mass and a decrease in muscle mass. For example, postpolio MA is muscle wasting that occurs as part of postpoliotic syndrome (PPS). Atrophy includes weakness, muscle fatigue, and pain.

Another type of MA is X-linked spinal muscular atrophy (SBMA - also known as Kennedy's disease). This disease occurs due to a defect in the androgen receptor gene on the X chromosome, affects only men, and its onset occurs from late adolescence to adulthood. The proximal limb and bulbar muscle weakness in some cases lead to physical limitations, including wheelchair dependence. Mutation leads to the expansion of the polyglutamine pathway in the N-terminal domain of the androgen receptor (polyQAR). The binding and activation of polyQAR by endogenous androgens (testosterone and DHT) leads to the unfolding and nuclear translocation of the mutant androgen receptor. These steps are necessary for pathogenesis and lead to a partial loss of transactivation function (i.e., insensitivity to androgens) and poorly understood neuromuscular degeneration. Currently, there is no cure that modifies the disease, but rather, only treatment for the symptoms. The efforts to target polyQAR as a proximal toxicity mediator by using cellular equipment to facilitate its degradation promise a therapeutic invention. Selective degrading androgen receptors, such as those described herein, bind and degrade various androgen receptors (full length, splice variant, antiandrogen resistant mutants, etc.), which indicates that they are promising for the treatment of SBMA. This view is supported by the observation that peripheral antisense polyQAR therapy eliminates SBMA disease in mouse models (CellReports 7, 774-784, May 8, 2014).

In one embodiment, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of Kennedy disease, comprising administering a therapeutically effective amount of a compound of Formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

As used herein, the term “androgen receptor-related conditions” or “androgen-sensitive diseases or disorders” are conditions, diseases or disorders that are modulated or whose pathogenesis depends on the activity of the androgen receptor. The androgen receptor is expressed in most tissues of the body, however, it is overexpressed in, among other things, the prostate gland and skin. ADT has been the basis for the treatment of prostate cancer for many years, and SARD can also be useful in the treatment of various prostate cancers, benign prostatic hypertrophy, prostatomegaly and other prostate diseases.

In one embodiment of the invention, the present invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of benign prostatic hypertrophy, comprising administering a therapeutically effective amount of a compound of formulas I-VII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment of the invention, the present invention relates to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of prostatomegaly, comprising administering a therapeutically effective amount of a compound of formulas I-VII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment of the invention, the present invention relates to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of hyperproliferative prostate diseases and diseases, comprising administering a therapeutically effective amount of a compound of formulas I-VII or its isomer, pharmaceutically acceptable salt, pharmaceutical product polymorph, hydrate, or any combination thereof. In another embodiment, the compound is any of compounds 13-21, 49, 50, and 17a.

The effect of AR on the skin is manifested in gender dimorphisms and dermatological problems associated with puberty, characteristic of adolescents and young adults. Puberty hyperandrogenism stimulates the growth of terminal hair, sebum production and predisposes male adolescents to acne, juvenile acne, seborrhea, excess sebum, hydradenitis, suppurative, hirsutism, hypertrichosis, superhairness, androgenetic alopecia, and other types of male pattern baldness. Although antiandrogens should theoretically prevent the discussed hyperandrogenic dermatological diseases, they are limited by toxicity, sexual side effects, and lack of efficacy when applied topically. The SARDs of this invention effectively inhibit ligand-dependent and ligand-independent activation of ARs and have short biological half-lives in serum, which indicates that locally formulated SARDs of the present invention can be applied to areas affected by acne, seborrheic dermatitis and / or hirsutism without the risk of systemic side effects.

In one embodiment, the invention is directed to a method of treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of acne, comprising administering a therapeutically effective amount of a compound of Formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment of the invention, the present invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of acne, comprising administering a therapeutically effective amount of a compound of formulas I-VII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of seborrhea, comprising administering a therapeutically effective amount of a compound of formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment of the invention, the invention is directed to a method of treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of suppository hydradenitis, comprising administering a therapeutically effective amount of a compound of formulas I-VII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment of the invention, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of hypertrichosis, comprising administering a therapeutically effective amount of a compound of formulas I-VII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment of the invention, the present invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of super-hairiness, comprising administering a therapeutically effective amount of a compound of formulas I-VII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment of the invention, the present invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of alopecia, comprising administering a therapeutically effective amount of a compound of formulas I-VII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment of the invention, the compounds described herein and / or compositions can be used for use in or treating hair loss, alopecia, androgenetic alopecia, alopecia areata, secondary alopecia in relation to chemotherapy, secondary alopecia in relation to radiation therapy, baldness, alopecia caused by scarring, or alopecia caused by stress. In one embodiment of the invention, “hair loss” or “alopecia” refers to baldness as a common type of male pattern baldness. Alopecia usually begins with hair loss in shreds on the scalp and sometimes progresses to complete baldness and even loss of body hair. Hair loss affects both men and women.

In one embodiment of the invention, the present invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of androgenetic alopecia, comprising administering a therapeutically effective amount of a compound of formulas I-VII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

The SARDs of this invention may also be useful in treating hormonal conditions in women, such as premature puberty, early puberty, dysmenorrhea, amenorrhea, multicellular uterine syndrome, endometriosis, hysteriomyoma, abnormal uterine bleeding, early menarche, fibrocystic breast disease , uterine fibroids, ovarian cysts, polycystic ovary syndrome, preeclampsia, eclampsia of pregnancy, premature birth, premenstrual syndrome and vaginal dryness.

In one embodiment of the invention, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of premature puberty or early puberty, comprising administering a therapeutically effective amount of a compound of formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment of the invention, the present invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of a multi-chamber uterus syndrome, endometriosis, uterine fibroids or abnormal uterine bleeding, comprising administering a therapeutically effective amount of a compound of formulas I-VII or its isomer , a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of any hyperandrogenic diseases (e.g., polycystic ovary syndrome (PCOS)), comprising administering a therapeutically effective amount of a compound of formula I-VII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment of the invention, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of fibrocystic breast disease, uterine fibroids, ovarian cysts or polycystic ovary syndrome, comprising administering a therapeutically effective amount of a compound of formula I- VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment of the invention, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of preeclampsia, eclampsia of pregnancy, premature birth, premenstrual syndrome or dry vagina, comprising administering a therapeutically effective amount of a compound of formulas I-VII or isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

The SARDs of the present invention can also be useful in treating sexual perversions, hypersexuality, paraphilia, androgenic psychosis, virilization, androgen insensitivity syndromes (AIS) such as complete AIS (CAIS) and partial AIS (PAIS), and improving ovulation in an animal.

In one embodiment, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of sexual perversions, hypersexuality or paraphilia, comprising administering a therapeutically effective amount of a compound of formulas I-VII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of virilization, comprising administering a therapeutically effective amount of a compound of formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment of the invention, the present invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of androgen insensitivity syndromes, comprising administering a therapeutically effective amount of a compound of formulas I-VII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a. In one embodiment, the androgen insensitivity syndrome is a syndrome of complete insensitivity to androgens. In another embodiment, the androgen insensitivity syndrome is a partial androgen insensitivity syndrome.

In one embodiment, the invention is directed to a method of increasing, modulating, or improving ovulation in an animal, comprising administering a therapeutically effective amount of a compound of Formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

The SARDs of this invention may also be useful for treating hormone-dependent cancers such as prostate cancer, breast cancer, testicular cancer, ovarian cancer and urogenital cancer, etc. In addition, topical or systemic administration of SARD may be useful for the treatment of hormone-dependent cancer precursors, such as prostate intraepithelial neoplasia (PIN) and atypical minor acinar proliferation (ASAP).

In one embodiment, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of breast cancer, comprising administering a therapeutically effective amount of a compound of Formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of testicular cancer, comprising administering a therapeutically effective amount of a compound of Formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment, the invention is directed to a method of treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of uterine cancer, comprising administering a therapeutically effective amount of a compound of Formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of ovarian cancer, comprising administering a therapeutically effective amount of a compound of Formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment of the invention, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of prostate cancer precursors, comprising topically or systemically administering a therapeutically effective amount of a compound of formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a. In one embodiment, the prostate cancer precursor is prostatic intraepithelial neoplasia (PIN). In another embodiment, the prostate cancer precursor is atypical small acinar proliferation (ASAP).

In one embodiment, the present invention relates to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of AR-linked solid tumors. In another embodiment, the tumor is hepatocellular carcinoma (HCC). In another embodiment, the tumor is bladder cancer. Serum testosterone may be positively associated with the development of HCC. Based on epidemiological, experimental observations and, in particular, the fact that men have a significantly higher risk of developing bladder cancer than women, androgens and / or AR also play a role in initiating bladder cancer.

The SARDs of the present invention may also be useful for the treatment of other malignant tumors containing AR, such as a tumor of the breast, brain, skin, ovary, bladder, lymphoma, liver, kidney, pancreas, endometrium, lung (e.g. NSCLC), perianal adenoma, osteosarcoma, central nervous system, melanoma, hypercalcemia of malignant neoplasms and metastatic bone diseases, etc.

In one embodiment of the invention, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of hypercalcemia of malignant neoplasms, comprising administering a therapeutically effective amount of a compound of formulas I-VII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment of the invention, the present invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of a metastatic bone disease, comprising administering a therapeutically effective amount of a compound of formulas I-VII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of brain cancer, comprising administering a therapeutically effective amount of a compound of Formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of skin cancer, comprising administering a therapeutically effective amount of a compound of Formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of bladder cancer, comprising administering a therapeutically effective amount of a compound of Formulas I-VII sludge and its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of lymphoma, comprising administering a therapeutically effective amount of a compound of Formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment of the invention, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of liver cancer, comprising administering a therapeutically effective amount of a compound of formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of kidney cancer, comprising administering a therapeutically effective amount of a compound of Formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment of the invention, the present invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of osteosarcoma, comprising administering a therapeutically effective amount of a compound of formulas I-VII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of pancreatic cancer, comprising administering a therapeutically effective amount of a compound of Formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment of the invention, the present invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of endometrial cancer, comprising administering a therapeutically effective amount of a compound of formulas I-VII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of lung cancer, comprising administering a therapeutically effective amount of a compound of formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a. In one embodiment, lung cancer is non-small cell lung cancer (NSCLC).

In one embodiment of the invention, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of cancer of the central nervous system, comprising administering a therapeutically effective amount of a compound of formulas I-VII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of colon cancer, comprising administering a therapeutically effective amount of a compound of formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment of the invention, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of melanoma, comprising administering a therapeutically effective amount of a compound of formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment of the invention, the invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of amyotrophic lateral sclerosis (ALS) in a subject, comprising administering a therapeutically effective amount of a compound of formulas I-VII or an isomer thereof, a pharmaceutically acceptable salt , pharmaceutical product, polymorph, hydrate, or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment of the invention, the present invention is directed to a method for treating, suppressing, reducing the incidence of a disease, reducing the severity or inhibiting the progression of uterine fibroids in a subject, comprising administering a therapeutically effective amount of a compound of formulas I-VII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment of the invention, the invention provides a method for treating a subject suffering from a wound or reducing the incidence of the disease, or alleviating the severity or strengthening, or accelerating wound healing in a subject, the method comprises administering to the subject a therapeutically effective amount of a compound of formulas I-VII or an isomer thereof , a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment of the invention, the invention provides a method of treating a subject suffering from a burn or reducing the incidence of the disease, or reducing the severity or worsening, or accelerating healing of a burn in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formulas I-VII or an isomer thereof , a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

Wounds and / or ulcers are usually found to protrude from the skin or onto the surface of the mucous membrane, or as a result of a heart attack in an organ. A wound may be the result of a soft tissue defect or lesion, or an underlying condition. In one embodiment of the invention, the term “wound” means bodily injury in violation of the normal integrity of tissue structures. The term is also intended to cover the terms pain, lesion, necrosis, and ulcer. In one embodiment of the invention, the term “pain” refers to any lesion of the skin or mucous membranes, and the term “ulcer” refers to a local defect or depression in the surface of an organ or tissue that forms when the necrotic tissue is flaked. Damage usually refers to any tissue defect. Necrosis is associated with dead tissue as a result of infection, trauma, inflammation or heart attacks. They are all covered by the term “wound”, which means any wound at any particular stage of the healing process, including the stage before any healing has begun or even before a specific wound has been made, such as a surgical incision (preventive treatment).

Examples of wounds that can be prevented and / or treated in accordance with the present invention are, for example, aseptic wounds, bruise wounds, incised wounds, lacerations, non-penetrating wounds (e.g., wounds in which there is no destruction of the skin, but there is damage main structures), open wounds, penetrating wounds, perforating wounds, puncture wounds, septic wounds, subcutaneous wounds, etc. Examples of ulcers are pressure sores, ulcerative stomatitis, skin ulcers, herpes, namin, etc. Examples of ulcers are, for example, peptic ulcer, duodenal ulcer, stomach ulcer, gout ulcer, diabetic ulcer, hypertensive ischemic ulcer, varicose ulcer, trophic ulcer (venous ulcer), sublingual ulcer, submucosal ulcer, tropic ulcer, ulcer ulcer , a venereal ulcer, for example, caused by gonorrhea (including urethritis, endocervicitis and proctitis). Conditions associated with wounds or ulcers that can be successfully treated in accordance with the invention are burns, anthrax, tetanus, gas gangrene, scarlet fever, erysipelas, common sycosis, folliculitis, contagious impetigo or bullous impetigo, etc. Often there is a certain correspondence between the use of the terms “wound” and “ulcer” and “wound” and “pain”, and in addition, the terms are often used randomly. Therefore, as mentioned above, in the present context, the term “wounds” encompasses the term “ulcer”, “lesion”, “pain” and “heart attack”, and the terms are used indiscriminately unless otherwise indicated.

The types of wounds to be treated in accordance with the invention also include: i) general wounds, such as, for example, surgical, traumatic, infectious, ischemic, thermal, chemical and bullous wounds; ii) oral-specific wounds, such as, for example, post-extraction wounds, endodontic wounds, especially those associated with the treatment of cysts and abscesses, ulcers and lesions of a bacterial, viral or autoimmunological origin, mechanical, chemical, thermal, infectious and lichenoid wounds; herpes ulcers, stomatitis aphthosis, acute necrotizing ulcerative gingivitis and burning syndrome, which are specific examples; and iii) skin wounds, such as, for example, neoplasm, burns (e.g. chemical, thermal), lesions (bacterial, viral, autoimmunological), bites and surgical incisions. Another way to classify wounds is: i) minor tissue loss due to surgical incisions, minor abrasions and small bites, or ii) significant tissue loss. The last group includes ischemic ulcers, pressure ulcers, fistulas, lacerations, serious bites, thermal burns and wounds of the donor site (in soft and hard tissues) and heart attacks.

In other aspects of the invention, the wound to be prevented and / or treated is selected from the group consisting of aseptic wounds, heart attacks, contusion wounds, cut wounds, lacerations, non-penetrating wounds, open wounds, penetrating wounds, perforating wounds, puncture wounds, septic wounds and subcutaneous wounds.

Other wounds that are important in connection with the present invention are wounds, such as ischemic ulcers, pressure ulcers, fistulas, severe bites, thermal burns, and donor site wounds.

Coronary and pressure ulcers are wounds that usually heal very slowly, and especially in such cases, improvement and faster healing, of course, is of great importance to the patient. In addition, the costs associated with treating patients suffering from such wounds are significantly reduced when treatment improves and occurs faster.

Wounds of the donor site are wounds that, for example, occur in connection with the removal of solid tissue from one part of the body to another part of the body, for example, in connection with transplantation. The wounds resulting from such operations are very painful, so the quickest healing is the most valuable.

The term “skin” is used in a very broad sense, covering the epidermal layer of the skin, and in cases where the surface of the skin is more or less damaged, also the dermal layer of the skin. In addition to the stratum corneum, the epidermal layer of the skin is the outer (epithelial) layer and a deeper layer of the connective tissue of the skin is called dermis.

Since the skin is the most exposed part of the body, it is particularly susceptible to various types of injuries, such as, for example, tears, cuts, abrasions, burns and frostbite, or injuries resulting from various diseases. In addition, a lot of skin is often destroyed in accidents. However, due to the important barrier and physiological function of the skin, skin integrity is important for human well-being and any disturbance or rupture is a threat that must be encountered by the body in order to protect its continued existence.

In addition to injuries to the skin, injuries can also be present in all types of tissues (i.e., soft and hard tissues). Injuries to soft tissues, including mucous membranes and / or skin, are particularly relevant in connection with the present invention.

A wound healing on the skin or on the mucous membrane undergoes a series of stages, which lead either to the restoration or regeneration of the skin or mucous membrane. In recent years, regeneration and recovery have been noted as two types of healing that can occur. Regeneration can be defined as a biological process, as a result of which the architecture and function of the lost tissue are completely updated. Recovery, on the other hand, is a biological process in which the continuity of destroyed tissue is restored by new tissues that do not replicate the structure and function of the lost.

Most wounds heal through repair, which means that the newly formed tissue is structurally and chemically unlike the original tissue (scar tissue). In the early stage of tissue repair, one of the processes that almost always participates is the formation of transitional connective tissue in the area of tissue damage. This process begins with the formation of a new extracellular collagen matrix by fibroblasts. This new extracellular collagen matrix is the support of connective tissue during the final healing process. The ultimate healing is, in most tissues, the formation of scars containing connective tissue. In tissues that have regenerative properties, such as, for example, skin and bone, final healing involves regeneration of the original tissue. This regenerated tissue often also has some scar characteristics, such as a thickening of the healed bone fracture.

Under normal conditions, the body provides mechanisms for treating damaged skin or mucous membranes in order to restore the integrity of the skin or mucous membrane barrier. The process of healing even minor ruptures or wounds can last from several hours to several weeks. However, with ulceration, healing can be very slow and the wound can persist for a long period of time, that is, months or even years.

Burns are associated with reduced testosterone levels, and hypogonadism is associated with a delay in wound healing. In one embodiment of the invention, the methods of the present invention provide for the treatment of a patient suffering from a wound or burn by administering a SARD in accordance with the present invention. In one embodiment of the invention, the SARD promotes the healing of a burn or wound, or in another embodiment of the invention participates in the healing process of a burn or wound, or in another embodiment of the invention treats a secondary complication of a burn or wound.

In one embodiment of the invention, the treatment of burns or wounds further includes the use of additional growth factors such as epidermal growth factor (EGF), transforming growth factor α (TGF-α), platelet growth factor (PDGF), fibroblast growth factors (FGF), including acidic fibroblast growth factor (α-FGF) and basic fibroblast growth factor (β-FGF), transforming β-growth factor (TGF-β) and insulin-like growth factors (IGF-1 and IGF-2), or any combination thereof that are promoters of wound healing.

Wound healing can be measured by many methods known in the art, including wound tensile strength, hydroxyproline or collagen content, expression of procollagen and re-epithelization. By way of example, SARD, as described herein, is administered orally or topically at a dose of about 0. 1-1 mg per day. Therapeutic efficacy is measured as efficacy in improving wound healing. Enhanced wound healing can be measured using known methods, such as reducing healing time, increasing collagen density, increasing hydroxyproline, reducing complications, increasing tensile strength and increasing cellularity of scar tissue.

In one embodiment of the invention, the terms “treat” or “treatment” include prophylactic as well as remitting treatment of the disorder. The terms "reduction", "suppression" and "inhibition" have the common meaning of decreasing or decreasing, in another embodiment of the invention, or delay, in another embodiment of the invention, or reducing, in another embodiment of the invention, the frequency, severity or pathogenesis of the disease, disorders or conditions. In an embodiment, the term “treatment” refers to delayed progression, prolonged remission, reduced morbidity, or ameliorated symptoms associated with a disease, disorder, or condition. In one embodiment of the invention, the terms “treatment”, “reduction”, “suppression”, or “inhibition” refer to a reduction in morbidity, mortality, or a combination thereof, in combination with said disease, disorder, or condition. In one embodiment of the invention, the term "progression" refers to an increase in the extent or severity, progress, growth or deterioration. The term “repetition” means, in another embodiment, the return of the disease after remission. In one embodiment of the invention, the methods of treatment of the invention reduce the severity of the disease, or, in another embodiment, the symptoms associated with the disease, or, in another embodiment, reduce the levels of biomarkers expressed during the disease.

In one embodiment of the invention, the term “treatment” and its included aspects refers to the administration to a subject with a specified disease, disorder or condition, or in some embodiments of the invention to a subject predisposed to said disease, disorder or condition. The term “predisposition” refers, in particular, to a genetic profile or family relationship associated with a tendency or statistical increase in incidence, severity, etc. the specified disease. In some embodiments, the term “predisposition” should be considered as referring, in particular, to a lifestyle that is associated with an increased risk of the disease. In some embodiments of the invention, the term “predisposition” should be considered as referring, in particular, to the presence of biomarkers that are associated with the disease, for example, in cancer, the term “predisposed to” cancer may include the presence of precancerous precursors for said cancer.

In some embodiments of the invention, the term “pathogenesis reduction” is to be understood as encompassing a reduction in tissue damage or organ damage associated with a particular disease, disorder or condition. In another embodiment, the term “reduction of pathogenesis” should be understood as encompassing a reduction in the incidence of a disease or the severity associated with a disease, disorder or condition of the disease, taking this issue into account. In another embodiment, the term “pathogenesis reduction” is to be understood as encompassing a reduction in the number of related diseases, disorders or conditions with the indicated or associated symptoms.

Pharmaceutical Compositions

In some embodiments of the invention, the present invention relates to methods of use, which include the introduction of a composition containing the described compounds. As used herein, the term “pharmaceutical composition” means a “therapeutically effective amount” of an active ingredient, that is, a compound of the present invention, together with a pharmaceutically acceptable carrier or diluent. As used herein, a “therapeutically effective amount” refers to that amount that provides a therapeutic effect for a given condition and administration regimen.

As used herein, the term “administration” refers to bringing a subject into contact with a compound of the present invention. As used here, the introduction can be carried out in vitro, that is, in vitro or in vivo, that is, in the cells or tissues of living organisms, for example, humans. In one embodiment of the invention, the present invention encompasses the administration of the compounds of the present invention to a male subject. In one embodiment, the present invention encompasses the administration of the compounds of the present invention to a female subject.

This invention provides, in other embodiments, pharmaceutical products of the compounds described herein. The term "pharmaceutical product", in other embodiments of the invention, refers to a composition suitable for pharmaceutical use (pharmaceutical composition), for example, as described herein.

The compounds of the invention may be administered alone or as an active ingredient in a preparation. Thus, the present invention also includes pharmaceutical compositions of the compounds of formulas I-VII, containing, for example, one or more pharmaceutically acceptable carriers.

There are numerous standard references that describe procedures for preparing various compositions suitable for administering the compounds of the invention. Examples of potential formulations and preparations are, for example, in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical dosage forms: Tablets (Lieberman, Lachmanand Schwartz, eds.) Current edition, published by Marcel Dekker, Inc., and Remington's Pharmaceutical Sciences (Arthur Osol, eds.), 1553-1593 (current edition).

The route of administration and dosage form are closely related to therapeutic amounts of the compounds or compositions that are desirable and effective for a given use for treatment.

Pharmaceutical compositions containing a compound of the present invention can be administered to a subject by any means known to a person skilled in the art, such as oral, parenteral, intravascular, paracancerous, transmucosal, transdermal, intramuscular, intranasal, intravenous, intradermal, subcutaneous, sublingual, intraperitoneal, intraventricular , intracranially, intravaginally, by inhalation, rectally, intramuscularly or by any means, in which the composition can be delivered to the tissue (for example, a needle or catheter). Alternatively, topical administration may be desirable for use on skin, ocular or mucous surfaces. Another route of administration is aspiration or an aerosol composition. In addition, in another embodiment of the invention, the pharmaceutical compositions may be administered topically on the surface of the body and are thus formulated in a form suitable for topical administration. Suitable topical formulations include gels, ointments, creams, lotions, drops, and the like. For topical administration, the compounds of the present invention or their physiologically tolerable derivatives, such as salts, esters, N-oxides and the like, are prepared and used in the form of solutions, suspensions or emulsions in a physiologically acceptable diluent with or without a pharmaceutical carrier.

Suitable dosage forms include, but are not limited to, oral, rectal, sublingual, mucous, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, spinal, intrathecal, intraarticular, intraarterial, subarachnoid, bronchial, lymphatic and other intrauterine administration forms for systemic delivery of active ingredients. In some applications, compositions suitable for oral administration are preferred. In some applications, compositions suitable for topical administration are preferred.

Topical administration: In a typical embodiment of the invention, the compounds of formulas I-VII are administered topically. Topical application is especially suitable for hirsutism, alopecia, acne and excess sebum. The dose will vary, but as a general guide, the compound will be present in a dermatologically acceptable carrier in an amount of about 0. 01 to 50 wt. % and more typically from about 0. 1 to 10 wt. % As a rule, a dermatological preparation is applied to the affected area from 1 to 4 times a day. “Dermatologically acceptable” refers to a carrier that can be applied to the skin or hair, and which will allow the drug to diffuse to the site of action. More specifically, this relates to the site where the androgen receptor is inhibited or the degradation of the androgen receptor is desired.

In a further embodiment of the invention, the compounds of formulas I-VII are used topically to alleviate alopecia, especially androgenetic alopecia. Androgens have a profound effect on both hair growth and hair loss. In most parts of the body, such as the beard and pubic skin, androgens stimulate hair growth, prolonging the phase of growth of the hair cycle (anagen) and increase the size of the follicle. Hair growth on the skin of the skull does not require androgens, but, paradoxically, androgens are necessary for baldness on the skin of the skull in genetically predisposed people (androgenic alopecia), where there is a gradual decrease in the duration of anagen and the size of the hair follicle. Androgenic alopecia is also common in women, where it usually represents diffuse hair loss, and does not show the pattern observed in men.

Although the compounds of formulas I-VII will most typically be used to alleviate androgenetic alopecia, the invention is not limited to this particular condition. The compounds of formulas I-VII can be used to alleviate any type of alopecia. Examples of non-androgenic alopecia include alopecia areata, alopecia due to radiation therapy or chemotherapy, cicatricial alopecia, stress-related alopecia, etc. As used in this application, “alopecia” refers to partial or complete hair loss on the scalp.

Thus, the compounds of formulas I-VII can be applied topically to the scalp and hair to prevent or alleviate baldness. In addition, the compound of formulas I-VII can be applied topically to stimulate or promote the growth or growth of hair on the scalp.

In a further embodiment, the compounds of formulas I-VII are applied topically to prevent hair growth in areas where such hair growth is undesirable. One such use will be to alleviate excessive hair growth. Excessive hair growth is excessive hair growth in areas that usually do not have hair (i.e. a female face). Such inappropriate hair growth is more common in women and is often observed with menopause. Topical administration of the compounds of formulas I-VII will alleviate this condition, leading to a reduction or elimination of this inappropriate or undesired hair growth.

The compounds of formulas I-VII may also be used topically to reduce sebum production. Sebum consists of triglycerides, wax esters, fatty acids, sterol esters and squalene. Sebum is formed in the acinar cells of the sebaceous glands and accumulates as these cells grow. Upon maturation, acinar cells are destroyed, transferring sebum to the lumen channel so that it can be deposited on the surface of the skin.

In some people, excess sebum is secreted on the skin. This can have a number of adverse effects. This can aggravate acne, as sebum is the main food source for Propionibacteriumacnes, the causative agent of acne. This can cause the skin to appear oily, which is generally considered cosmetically unappealing.

The formation of sebum is regulated by growth factors and various hormones, including androgens. The cellular and molecular mechanism by which androgens exert their influence on the sebaceous gland has not been fully elucidated. However, clinical experience indicates the effect of androgens on sebum production. Sebum production increases significantly during puberty, when androgen levels are highest. Thus, the compounds of formulas I-VII inhibit the secretion of sebum and thus reduce the amount of sebum on the surface of the skin. The compounds of formulas I-VII can be used to treat various skin diseases, such as acne or seborrheic dermatitis.

In addition to treating diseases associated with the formation of excess sebum, the compounds of formulas I-VII can also be used to achieve a cosmetic effect. Some consumers believe that they suffer from overactive sebaceous glands. They feel that their skin is oily and therefore unattractive. These individuals can use the compounds of formulas I-VII to reduce the amount of sebum on the skin. Decreased sebum secretion will alleviate oily skin in individuals affected by such conditions.

The compounds of formulas I-VII of the present invention are usually administered topically. As used herein, the term “local” refers to the use of compounds of formulas I-VII (and an additional carrier) directly on the skin and / or hair. The topical composition in accordance with the present invention may be in the form of solutions, lotions, ointments, creams, ointments, liposomes, sprays, gels, foams, roller sticks and any other composition commonly used in dermatology.

Thus, another embodiment of the invention relates to cosmetic or pharmaceutical compositions, in particular dermatological compositions, which contain at least one of the compounds corresponding to formulas I-VII described above. Such dermatological compositions will contain from 0. 001 to 10% wt. / wt. % of compounds in a mixture with a dermatologically acceptable carrier and more typically from 0. 1 to 5 wt. / wt. % compounds. Such compositions are usually applied 1 to 4 times per day. The reader's attention was drawn to Remington's Pharmaceutical Science, Edition 17, Mark Publishing Co., Easton, PA for a discussion of how to prepare such formulations.

Compositions in accordance with the invention may also consist of solid preparations constituting cleansing soaps or plates. These compositions are prepared in accordance with conventional methods.

The compounds of formulas I-VII can also be used for hair in the form of aqueous, alcoholic or aqueous-alcoholic solutions, or in the form of creams, gels, emulsions or mousses, or, alternatively, in the form of aerosol compositions also containing a propellant under pressure. The composition in accordance with the invention may also be a hair care composition and, in particular, shampoo, hair lotion, treatment lotion, styling cream or gel, a dye composition, lotion or gel to prevent hair loss, etc. The amounts of the various constituents in the dermatological compositions of the invention are those which are commonly used in the subject areas.

Medicines and cosmetics containing compounds of formulas I-VII will typically be packaged for retail sale (i.e., manufactured products). Such products will be labeled and packaged in such a way as to instruct the patient how to use the product. Such instructions will include the condition to be treated, duration of treatment, dosing schedule, etc.

Antiandrogens such as finasteride or flutamide have been shown to reduce androgen activity or block the action of androgen in the skin to some extent, but suffer from unwanted systemic effects. An alternative approach is topical application of the selective androgen receptor disruptor (SARD) for the affected areas. In one embodiment of the invention, such a SARD compound exhibits strong but local inhibition of AP activity. In another embodiment, the SARD compound exhibits strong but local degradation of AR activity. In another embodiment, the SARD compound will not enter the systemic circulation of the subject. In another embodiment, the SARD compound is rapidly metabolized when it enters the bloodstream, which limits systemic exposure.

To prepare such pharmaceutical dosage forms, the active ingredient may be mixed with a pharmaceutical carrier in accordance with conventional pharmaceutical mixing methods. The carrier may take a variety of forms, depending on the form of the drug desired for administration.

As used herein, “pharmaceutically acceptable carriers or diluents” are well known to those skilled in the art. The carrier or diluent may be a solid carrier or diluent for solid forms, a liquid carrier or diluent for liquid compositions or mixtures thereof.

Solid carriers / diluents include, but are not limited to, resin, starch (e.g., corn starch, pregelatinized starch), sugar (e.g., lactose, mannitol, sucrose, dextrose), cellulosic material (e.g. microcrystalline cellulose), acrylate (e.g. polymethylacrylate), calcium carbonate, magnesium oxide, talc or a mixture thereof.

Oral or parenteral administration. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be used. Thus , for liquid oral preparations, such as, for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavors, preservatives, colorants and the like. For solid oral preparations, such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most preferred oral dosage unit form. If desired, tablets may be sugar coated or enteric coated by standard methods.

For parenteral compositions, the carrier will usually contain sterile water, although other ingredients, for example, ingredients that promote solubility or preservation, may be included. Injectable solutions may also be prepared, in which case appropriate stabilizing agents may be used.

In some applications, it may be advantageous to use the active agent in a “vectorized” form, such as encapsulating the active agent in a liposome or other encapsulating medium, or by fixing the active agent, for example, by covalent binding, chelation or associative coordination on a suitable biomolecule, such as those which are selected from proteins, lipoproteins, glycoproteins and polysaccharides.

The methods of treatment of the present invention using compositions suitable for oral administration can be presented in separate units, such as capsules, cachets, tablets or lozenges, each of which contains a predetermined amount of the active ingredient in the form of, for example, powder or granules. If necessary, a suspension in an aqueous solution or a non-aqueous liquid, such as a syrup, elixir, emulsion or precipitate, can be used.

A tablet may be made by compression or molding, or by wet granulation, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compression in a suitable machine, the active compound being in a free-flowing form, such as powder or granules, which, if necessary, are mixed, for example, with a binder, disintegrant, lubricant, inert diluent, surface active agent or discharging agent agent. Molded tablets consisting of a mixture of the powdered active compound with a suitable carrier can be made by molding in a suitable machine.

A syrup can be obtained by adding the active compound to a concentrated aqueous solution of sugar, for example, sucrose, to which any auxiliary ingredient (s) can also be added. Such auxiliary ingredient (s) may include flavorings, a suitable preservative, agents to slow the crystallization of sugar, and agents to increase the solubility of any other ingredient, such as a polyhydroxy alcohol, for example glycerol or sorbitol.

Formulations suitable for parenteral administration may contain a sterile aqueous preparation of the active compound, which is preferably isotonic with the blood of the recipient (e.g., physiological saline). Such compositions may include suspending agents and thickeners and liposomes or other microparticle systems that are designed to target blood components or one or more organs. Drugs can be presented in the form of a single dose or in the form of several doses.

Parenteral administration may include any suitable form of systemic delivery. The administration may be, for example, intravenous, intraarterial, intrathecal, intramuscular, subcutaneous, intramuscular, intraperitoneal (e.g., intraperitoneal), etc. and may be carried out by infusion pumps (external or implantable) or by any other appropriate means suitable for the desired route of administration.

Preparations for the nose and other mucous membranes (for example, inhalation forms) may contain purified aqueous solutions of the active compounds with preservatives and isotonic agents. Such compositions are preferably adjusted to a pH and isotonic state compatible with the nasal or other mucous membranes. Alternatively, they may be in the form of finely divided solid powders suspended in a gas carrier. Such compositions may be delivered by any suitable means or method, for example, using a nebulizer, atomizer, metered dose inhaler or the like.

Formulations for rectal administration may be presented as a suppository with a suitable carrier, such as cocoa butter, hydrogenated fats or hydrogenated fatty carboxylic acids.

Transdermal preparations can be prepared by incorporating the active agent in a thixotropic or gelatinous carrier, such as a cellulosic medium, for example methyl cellulose or hydroxyethyl cellulose, the resulting preparation then being packaged in a transdermal device adapted to guarantee skin contact with the user's skin.

In addition to the above ingredients, the compositions of the present invention may additionally include one or more additional ingredients selected, for example, from diluents, buffers, flavors, binders, disintegrants, surfactants, thickeners, lubricants, preservatives (including antioxidants) etc.

The compositions of the present invention may have immediate release, sustained release, delayed release, or any other release profile known to one skilled in the art.

It should be understood that this invention encompasses any embodiment of a compound as described herein, which in some embodiments relates to a “compound of the present invention.”

For administration to mammals and, especially, humans, it is expected that the physician will determine the actual dose and duration of treatment, which will be most suitable for the individual and may vary depending on the age, weight and response of a particular person.

In one embodiment, the methods of the present invention may include administering the compounds of the present invention in various doses. In one embodiment, the compound of this invention is administered at a dose of 1-3000 mg per day. In an additional embodiment of the invention, the compound of this invention is administered at a dose of 1-10 mg per day, 3-26 mg per day, 3-60 mg per day, 3-16 mg per day, 3-30 mg per day, 10-26 mg per day, 15-60 mg, 50-100 mg per day, 50-200 mg per day, 100-250 mg per day, 125-300 mg per day, 20-50 mg per day, 5-50 mg per day , 200-500 mg per day, 125-500 mg per day, 500-1000 mg per day, 200-1000 mg per day, 1000-2000 mg per day, 1000-3000 mg per day, 125-3000 mg per day, 2000-3000 mg per day, 300-1500 mg per day or 100-1000 mg per day. In one embodiment, the compound of this invention is administered at a dose of 25 mg per day. In one embodiment, the compound of this invention is administered at a dose of 40 mg per day. In one embodiment, the compound of this invention is administered at a dose of 50 mg per day. In one embodiment, the compound of this invention is administered at a dose of 67.5 mg per day. In one embodiment, the compound of this invention is administered at a dose of 75 mg per day. In one embodiment, the compound of this invention is administered at a dose of 80 mg per day. In one embodiment, the compound of this invention is administered at a dose of 100 mg per day. In one embodiment, the compound of this invention is administered at a dose of 125 mg per day. In one embodiment, the compound of this invention is administered at a dose of 250 mg per day. In one embodiment, the compound of this invention is administered at a dose of 300 mg per day. In one embodiment, the compound of this invention is administered at a dose of 500 mg per day. In one embodiment, the compound of this invention is administered at a dose of 600 mg per day. In one embodiment, the compound of this invention is administered at a dose of 1000 mg per day. In one embodiment, the compound of this invention is administered at a dose of 1,500 mg per day. In one embodiment, the compound of this invention is administered at a dose of 2000 mg per day. In one embodiment, the compound of this invention is administered at a dose of 2500 mg per day. In one embodiment, the compound of this invention is administered at a dose of 3000 mg per day. In another embodiment, the compound is any one of compounds 13-21, 49, 50, and 17a.

In one embodiment of the invention, the methods of the present invention provide for the use of a pharmaceutical composition comprising a compound of formulas I-VII. In additional embodiments of the invention, the methods of the present invention involve the use of a pharmaceutical composition comprising a compound of formula I, formula II, formula III, formula IV or formula V, formula VI or formula VII, or any of compounds 13-21, 49, 50, and 17a.

In a particular embodiment, the pharmaceutical composition is in solid dosage form. In another embodiment, the pharmaceutical composition is a tablet. In another embodiment, the pharmaceutical composition is a capsule. In another embodiment, the pharmaceutical composition is a solution. In another embodiment, the pharmaceutical composition is a transdermal patch.

In one embodiment, the use of a compound of the present invention or a composition containing it will be useful in inhibiting, suppressing, enhancing, or stimulating a desired response in a subject, as one skilled in the art will recognize. In another embodiment of the invention, the compositions may further comprise additional active ingredients whose activity is useful for the particular application for which the compound of the present invention is administered.

For administration to mammals, and especially humans, it is expected that the physician will determine the actual dose and duration of treatment, which will be most suitable for the individual and may vary depending on the age, weight, genetics and / or response of a particular person.

In some embodiments of the invention, any of the compositions of the present invention will contain a compound of the present invention in any form or embodiment of the invention, as described herein. In some embodiments of the invention, any of the compositions of the present invention will consist of a compound of the present invention in any form or embodiment of the invention as described herein. In some embodiments, the compositions of the present invention will consist essentially of a compound of the present invention in any form or embodiment of the invention as described herein. In some embodiments of the invention, the term “includes” refers to the inclusion of said active agent, such as a compound of the present invention, as well as the inclusion of other active agents and pharmaceutically acceptable carriers, excipients, emollients, stabilizers, etc., as is known in the pharmaceutical industry. In some embodiments of the invention, the term “consisting essentially of” refers to a composition whose sole active ingredient is the specified active ingredient, but other compounds that are intended to stabilize, maintain, etc., may be included. composition, but not directly related to the therapeutic effect of the specified active ingredient. In some embodiments, the term “consisting essentially of” may refer to components that facilitate the release of the active ingredient. In some embodiments, the term “consisting” refers to a composition that contains an active ingredient and a pharmaceutically acceptable carrier or excipient.

It should be understood that any use of any of the compounds described herein can be used to treat any disease, disorder or condition, as described herein, and is an embodiment of the present invention. In one embodiment of the invention, the compounds are free base, free acid, uncharged or non-complex compound.

The following examples are presented to more fully illustrate preferred embodiments of the invention. However, they should in no way be construed as limiting the broad scope of the invention.

Examples

Example 1

Synthesis of (S) -3- (substituted phenylamino) -N- (4-nitro- or 4-cyano-3- (trifluoromethyl) phenyl) -2-hydroxy-2-methylpropanamides (Compounds 12-19)

Scheme 1. Synthesis of (S) -3- (substituted phenylamino) -N- (4-nitro- or 4-cyano-3- (trifluoromethyl) phenyl) -2-hydroxy-2-methylpropanamides (12 ~ 19).

(2R) -1-methacryloylpyrrolidine-2-carboxylic acid (2).

D-proline (14.93 g, 0.13 mol) was dissolved in 71 ml of 2n NaOH and cooled in an ice bath. The resulting alkaline solution was diluted with acetone (71 ml). A solution of methacryloyl chloride in acetone (71 ml) (13.56 g, 0.13 mol) and a 2N NaOH solution (71 ml) were simultaneously added over 40 minutes to an aqueous solution of D-proline in an ice bath. The temperature of the mixture was maintained at 10-11 ° C. while methacryloyl chloride was added. After stirring (3 hours, room temperature (RT)), the mixture was evaporated in vacuo at a temperature of 35-45 ° C to remove acetone. The resulting solution was washed with ethyl ether and acidified to pH2 with concentrated HCl. The acidic mixture was saturated with NaCl and extracted with EtOAc (100 ml × 3). The combined extracts were dried over Na2SO4, filtered through Celite® and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexane afforded 16.2 g (68%) of the target compound as colorless crystals: mp. 102.1-103.4 ° C (lit. 102.5-103.5 ° C); The NMR spectrum of this compound demonstrated the existence of two rotamers of the title compound.

1NMR (300 MHz, DMSO-d6) δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (ultimately 2H for both rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for the second rotamer (ultimately 1H for both rotamers, CH near the chiral center), 3.57-3.38 (m, 2H, CH2), 227-2. 12 (1H, CH), 1.97-1.72 (m, 6H, CH2, CH, Me); 13NMR (75 MHz, DMSO-d6) δ for the major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for the minor rotamer 174.0, 170, 0, 1416, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C = O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm-1; [α]D26 + 80.8 ° (c = 1, MeOH); Calculated for C9H13NO3C 59.00; H 7.15; N 7.65. Found: C, 59.13; H, 7.19; N, 7.61.

(3R, 8aR) -3-bromomethyl-3-methyltetrahydropyrrolo [2,1-c] [1,4] oxazine-1,4-dione (3).

A solution of NBS (235 g, 0.132 mol) in 100 ml of DMF was added dropwise to a stirred solution of (methyl acryloyl) -pyrrolidine (16.1 g, 88 mmol) in 70 ml of DMF in argon atmosphere at RT and the resulting mixture was stirred for 3 days . The solvent was removed in vacuo and a yellow solid precipitated. The solid was suspended in water, stirred overnight at room temperature, filtered and dried to give 18.6 g (81%) (less weight on drying ~ 34%) of the title compound as a yellow solid: mp. 158.1-160.3 ° C;

1NMR (300 MHz, DMSO-d6) δ 469 (dd, J = 9.6 Hz, J = 6.7 Hz, 1H, CH near the chiral center), 4.02 (d, J = 11.4 Hz, 1H, CHHa), 3.86 (d, J = 11.4 Hz, 1H, CHHb), 3.53-3.24 (m, 4H, CH2), 2.30-2.20 (m, 1H, CH), 2.04-1.72 (m, 3H, CH2 and CH), 1.56 (s, 2H, Me); 13C NMR (75 MHz, DMSO-d6) δ 167.3, 163.1, 83.9, 57.2, 45.4, 37.8, 29.0, 22.9, 21.6; IR (KBr) 3474, 1745 (C = O), 1687 (C = O), 1448, 1377, 1360, 1308, 1227, 1159, 1062 cm-1; [α]D26 + 124.5 ° (c = 1.3, chloroform); Calculated for C9H12Brno3: C 41. 24, H 4. 61, N 5. 34. Found: C 41. 46, H 4. 64, N 5. 32.

(2R) -3-bromo-2-hydroxy-2-methylpropanoic acid (4).

A mixture of bromolactone (18.5 g, 71 mmol) in 300 ml of 24% HBr was heated under reflux for 1 hour. The resulting solution was diluted with brine (200 ml) and extracted with ethyl acetate (100 ml × 4). The combined extracts were washed with saturated NaHCO3 (100 ml × 4). The aqueous solution was acidified with concentrated HCl to pH = 1, which, in turn, was extracted with ethyl acetate (100 ml × 4). The combined organic solution was dried over Na2SO4, filtered through Celite® and evaporated in vacuo to dryness. Recrystallization from toluene afforded 10.2 g (86%) of the target compound as colorless crystals: mp. 110.3-113.8 ° C;

1NMR (300 MHz, DMSO-d6) δ 3.63 (d, J = 10.1 Hz, 1H, CHHa), 3.52 (d, J = 10.1 Hz, 1H, CHHb), 1.35 (d, 3H, Me); IR (KBr) 3434 (OH), 3300-2500 (COOH), 1730 (C = O), 1449, 1421, 1380, 1292, 1193, 1085 cm-1; [α]D26 + 105 ° (c = 2.6, MeOH); Calculated for C4H7Bro3C 26.25 H 3.86. Found: C, 26.28; H, 3.75.

(2R) -3-bromo-N- [4-cyano-3- (trifluoromethyl) phenyl] -2-hydroxy-2-methylpropanamide (8).

Thionyl chloride (4602 g, 0. 39 mol) was added dropwise to a cooled solution (less than 4 ° C) of (R) -3-bromo-2-hydroxy-2-methylpropanoic acid (51.13 g, 0.8 mol) in 300 ml THF in argon atmosphere. The resulting mixture was stirred for 3 hours under the same conditions. To this was added Et3N (3914 g, 0. 39 mol) and stirred for 20 min under the same conditions. After 20 minutes, 5-amino-2-cyanobenzotrifluoride (40.0 g, 0.21 mol), 400 ml of THF were added, and then the mixture was allowed to stir overnight at room temperature. The solvent was removed under reduced pressure to obtain a solid, which was treated with 300 ml of H2O, was extracted with EtOAc (2 × 400 ml). The combined organic extracts were washed with saturated NaHCO3 (2 × 300 ml) and brine (300 ml). The organic layer was dried over MgSO4 and concentrated under reduced pressure to obtain a solid which was purified from column chromatography using CH2Cl2/ EtOAc (80:20) to obtain a solid. This solid was recrystallized from CH.2Cl2/ hexane to give 55.8 g (73.9%) of (2R) -3-bromo-N- [4-cyano-3- (trifluoromethyl) phenyl] -2-hydroxy-2-methylpropanamide as a pale yellow solid . T. pl. 134.0-136.5 ° C;

1NMR (CDCl3/ TMS) δ 1.66 (s, 3H, CH3), 311 (s, 1H, OH), 3.63 (d, J = 10.8 Hz, 1H, CH2), 4.05 (d, J = 10.8 Hz, 1H, CH2), 7.85 (d, J = 8.4 Hz, 1H, ArH), 7.99 (dd, J = 2.1, 8.4 Hz, 1H, ArH), 8.12 (d, J = 2.1 Hz, 1H, ArH); 9.04 (br s, 1H, NH). MS (ESI) 349.0 [M - H]-; M. p. : 124-126ºC.

Preparation of 4-cyano-2, 3-substituted anilines (26-28)

Scheme 2. Preparation of 4-cyano-2, 3-substituted anilines (26-28).

General procedure I: arylaniline 24 (4.46 mmol), boric acid 25 (4.46 mmol), Pdcat (0.224 mmol, as shown in Scheme 2) and K2PO4 (8.92 mmol) in 10 ml of 1,4-dioxane was refluxed under argon overnight. The mixture was cooled to room temperature and poured into DCM, which was washed with water, dried over anhydrous MgSO4 and evaporated to dryness. The mixture was purified by flash column chromatography using EtOAc / hexane as the eluent, and then the condensed compounds were then recrystallized from EtOAc / hexane to give the desired products (26-28).

5-amino- [1, 1'-biphenyl] -2-carbonitrile (26)

Yield 80%; Brown solid; MS (ESI) 192.8 [M - H]-; 217.1 [M + Na]+; 1H NMR (CDCl3, 400 MHz) δ 7.54-7.42 (m, 6H), 6.71 (d, J = 3.2 Hz, 1H), 6.66 (dd, J = 11.2, 3.2 Hz , 1H), 4.22 (broad s, 2H, NH2).

6-amino- [1,1'-biphenyl] -3-carbonitrile (27)

Yield 79%; Brown solid; MS (ESI) 192.8 [M - H]-; 217.1 [M + Na]+; 1H NMR (CDCl3, 400 MHz) δ 7.50-730 (m, 7H), 6. 76 (dd, J = 11.2, 6.0 Hz, 1H), 4.27 (br s, 2H, NH2).

5-amino-4'-fluoro- [1,1'-biphenyl] -2-carbonitrile (28)

Yield 98%; Brown solid; MS (ESI) 200.8 [M - H]-; 1H NMR (DMSO-d6, 400 MHz) δ 7.50-748 (m, 3H), 7. 34-7.30 (m, 2H), 6.63 (m, 2H), 6.26 (br s, 2H, NH2).

Obtaining several 2-hydroxy-2-methylpropanamides (12-19)

General Procedure II:

Stage 1. Obtaining (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -2-methyloxyran-2-carboxamide (10) in THF: a mixture of hydroxyl bromide 8 (1.0 g, 2.84 mmol) and potassium carbonate (790 mg, 5.70 mmol) in 60 ml of acetone was heated under reflux for 30 minutes. After complete conversion of the starting bromide 8 to the desired epoxide 10, monitored by TLC, the solvent was evaporated under reduced pressure to give a yellowish precipitate, which was poured into 20 ml of anhydrous EtOAc. The solution was filtered through a Celite® pad to remove residue K2CO3 and condensed under reduced pressure to obtain a yellowish solid of epoxide 10, which was dissolved in 5 ml of anhydrous THF to obtain a solution of epoxide 10 in THF. The resulting solution was directly used as the next reagent without analysis.

Stage 2. NaH 60% dispersion in mineral oil (228 mg, 5.7 mmol) was added to 30 ml of anhydrous THF solvent in a 100 ml dry two-necked round-bottom flask equipped with a dropping funnel. Substituted aniline 11 (2.84 mmol) was added to the solution in an argon atmosphere in an ice bath, and the resulting solution was stirred for 30 minutes in an ice bath. A prepared solution of epoxide 9 or 10 (2.84 mmol in THF) was added to the flask through a dropping funnel in an argon atmosphere in an ice bath and stirred overnight at RT. After adding 1 ml of H2O the reaction mixture was condensed under reduced pressure and then dispersed in 50 ml EtOAc, washed (50 ml × 2) with water, brine, dried over anhydrous MgSO4 and evaporated to dryness. The mixture was purified by flash column chromatography using EtOAc / hexane as the eluent, and then the condensed compounds were then recrystallized from EtOAc / hexane to give the corresponding desired products 12 ~ 19.

Getting SARD12-19:

Scheme 3. Obtaining SARD 12-19.

(S) -N- (4-Cyano-3- (trifluoromethyl) phenyl) -3 - ((4-cyanophenyl) amino) -2-hydroxy-2-methylpropanamide (12)

Yield 58%; Brown solid; MS (ESI) 387.2 [M - H]-; 1H NMR (DMSO-d6, 400 MHz) δ 10.42 (broad s, 1H, NH), 8.11 (s, 1H), 8.21 (d, J = 22 Hz, 1H), 8. 01 (d, J = 2, 2 Hz, 1H), 7.38 (d, J = 8.7, 2H), 6.75 (d, J = 8.7 Hz, 2H), 6.12 (br s, 1H, NH), 3 61 (m, 1H); 3.25 (m, 1H); 2.29 (br s, 1H, OH); 1.42 (s, 3H); Calculated for C19H15F3N4O2: C, H, N.

(S) -N- (4-Cyano-3- (trifluoromethyl) phenyl) -3 - ((4-cyanonaphthalen-1-yl) amino) -2-hydroxy-2-methylpropanamide (13)

Yield 39%; Brown solid; MS (ESI) 437.2 [M - H]-; 1H NMR (CDCl3, 400 MHz) δ 914 (broad s, 1H, NH), 8.5 (d, J = 8.3 Hz, 1H), 8. 06 (d, J = 1.8 Hz, 1H), 7.98 ( dd, J = 8.3, 1.8 Hz, 1H), 7.82-7.71 (m, 5H), 6.70 (d, J = 81 Hz, 1H), 5. 51 (br s, 1H, NH), 3.95 (m, 1H), 3.57 (m, 1H), 2.29 (br s, 1H, OH), 1.74 (s, 3H); Calculated for C23H17F3N4O2: C, H, N.

(S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3 - ((6-cyano [1,1'-biphenyl] -3-yl) amino) -2-hydroxy-2-methylpropanamide ( fourteen)

Yield 42%; Brown solid; MS (ESI) 463.0 [M - H]-; 1H NMR (DMSO-d6, 400 MHz) δ 10.50 (broad s, 1H, NH), 8.46 (d, J = 2.0 Hz, 1H), 817 (dd, J = 8.4, 2.0 Hz, 1H) , 8.08 (d, J = 8.4 Hz, 1H), 7.47 (m, 6H), 6.75 (m, 1H), 6.58 (m, 1H), 6.13 (br s , 1H, NH), 3.67 (d, J = 14.8 Hz, 1H), 3.31 (d, J = 14.8 Hz, 1H), 2.49 (br s, 1H, OH), 1.24 (s, 3H); Calculated for C25H19F3N4O2: C, H, N.

(S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3 - ((5-cyano [1,1'-biphenyl] -2-yl) amino) -2-hydroxy-2-methylpropanamide ( 15)

Yield 32%; brown solid; MS (ESI) 462.9 [M - H]-; 487.1 [M + Na]+; 1H NMR (CDCl3, 400 MHz) δ 10.49 (broad s, 1H, NH), 8.45 (m 1H), 8.17-7.43 (m, 7H), 7.23 (m, 2H), 6.52 (m, 1H), 6.18 (br s, 1H, NH), 3.67 (d, J = 14.8 Hz, 1H), 3.31 (d, J = 14.8 Hz, 1H), 247 (br s, 1H, OH); 1.23 (s, 3H); Calculated for C25H19F3N4O2: C, H, N.

Scheme 4. Obtaining SARD 17-19 and 17a.

General Procedure III: A mixture of compounds 12 or 14 (0.15 mmol) and 0.5 ml of an alkyl halide (methyl iodide, n-propyl bromide or benzyl bromide) with 1 ml of N, N-diisopropylethylamine (DIPEA, Hyunig base) was loaded into a vessel with a lid. The reaction vessels were placed in a reactor block in a microwave oven. A programmed cycle of microwave irradiation was performed for 30 min (300 W) at 150 ° C and 25 min (fan cooling) (irradiation time - 30 min). The mixture was transferred to a round bottom flask for concentration under reduced pressure and poured into EtOAc, which was washed with water and dried over anhydrous MgSO4, concentrated, purified by silica gel chromatography (EtOAc / n-hexane) to obtain the desired products (17, 17a, 18 and 19).

(S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3 - ((6-cyano [1,1'-biphenyl] -3-yl) (methyl) amino) -2-hydroxy-2 methylpropanamide (17)

Yield 42%; Yellowish solid; MS (ESI) 501.1 [M + Na]+; 1H NMR (CDCl3, 400 MHz) δ 9.09 (br s, 1H, NH), 8.06 (s, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.79-7.28 (m, 7H), 6.88 (m, 2H), 3.98 (d, J = 15.6 Hz, 1H), 3.75 ( d, J = 15.6 Hz, 1H), 3.01 (s, 3H), 2.06 (s, 1H, OH), 1.63 (s, 3H); Calculated for C26H21F3N4O2: C, H, N.

(S) -3- (Benzyl (4-cyanophenyl) amino) -N- (4-cyano-3- (trifluoromethyl) phenyl) -2-hydroxy-2-methylpropanamide (18)

Yield 32%; Brown solid; MS (ESI) 476.9 [M - H]-; 501.1 [M + Na]+; 1H NMR (CDCl3, 400 MHz) δ 10.22 (broad s, 1H, NH), 8.35 (s, 1H), 8.17 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.20-7.11 (m, 5H), 6.75 (m, 1H), 6.91 (m, 2H), 6.23 (s, 1H), 4, 90 (s, 2H), 3.99 (d, J = 14.8 Hz, 1H), 3.89 (d, J = 14.8 Hz, 1H), 3.42 (br s, 1H, OH) 1.41 (s, 3H); Calculated for C26H21F3N4O2: C, H, N.

(S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3 - ((6-cyano-4'-fluoro- [1,1'-biphenyl] -3-yl) (methyl) amino) -2-hydroxy-2-methylpropanamide (19)

Yield 38%; Brown solid; MS (ESI) 495.2 [M - H]-; 1NMR (CDCl3, 400 MHz) δ 10.17 (broad s, 1H, NH), 8.15 (s, 1H), 8.00 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.49-7.48 (m, 4H), 7.34-7.30 (m, 2H), 6.75 (m, 1H), 3.99 (d, J = 14.8 Hz, 1H), 3.79 (d, J = 14.8 Hz, 1H), 3.09 (s, 3H), 2.11 (br s, 1H, OH), 1.61 ( s, 3H); Calculated for C26H20F4N4O2: C, H, N.

Example 1A

Synthesis of Compounds 14 and 17

Scheme 5. Obtaining SARD14 and 17. Reagents and conditions: (a) NaH, THF, 0ºC ~ RT; (b) CH3I, N, N-diisopropylethylamine, 120ºC, microwave.

Hydroxybromide 8 was used as an important intermediate, which was reacted with aniline 26 after activating NaH in a THF solvent to obtain 14. N-Alkylation 14 was a reaction using microwaves and was carried out under basic conditions using N, N-diisopropylethylamine (Hunig base ) to generate 17.

Example 1B

Synthesis of Compounds 49 and 50

General procedure: obtaining compounds 49 and 50

A mixture of phenyl trifluoromethanesulfonate (500 mg, 2.21 mmol), palladium (II) acetate (50 mg, 0.22 mmol), (±) 22'-bis (diphenylphosphino) -1,1'-binaphthyl (317 mg, 0, 66 mmol) and cesium carbonate (1.09 g, 3.31 mmol) in 50 ml of toluene were inertized with argon. Then 4-nitroaniline (331 mg, 2.43 mmol) or 4-fluoroaniline (2.43 mmol) was added and the mixture was heated at 110 ° C. overnight. The reaction was allowed to cool to room temperature and filtered through a pad of Celite®. The filtrate was diluted with CH2Cl2 and water. The phases were separated and the aqueous phase was re-extracted 2 times with CH2Cl2. The combined organic phases were dried over Na2SO4 and the resulting solution was dried over anhydrous Na2SO4 and purified by flash column chromatography using EtOAc / hexane (1/6, v / v) as eluent to give 4-nitro-N-phenylaniline or 4-fluoro-N-phenylaniline.

NaH 60% dispersion in mineral oil (228 mg, 5.7 mmol) was added to 20 ml of anhydrous THF solvent in a 100 ml dry two-necked round-bottom flask equipped with a dropping funnel and NH (Ph) (Ar) [Ar = 4-fluorophenyl; 4-nitrophenyl] (2.84 mmol) was added to the solution in an argon atmosphere in an ice water bath, and the resulting solution was stirred for 30 minutes in an ice water bath. Epoxy 10 (2.84 mmol in THF) was added to the flask through a dropping funnel in an argon atmosphere in an ice bath and stirred overnight at room temperature. After adding 1 ml of H2O the reaction mixture was condensed under reduced pressure and then dispersed in 50 ml EtOAc, washed with 50 ml (× 2) water, brine, dried over anhydrous MgSO4 and evaporated to dryness. The mixture was purified by flash column chromatography using EtOAc / hexane as the eluent, and then the condensed compounds were then recrystallized from EtOAc / hexane to give the desired product 49 or 50.

(S) -N- (4-Cyano-3- (trifluoromethyl) phenyl) -3 - ((4-fluorophenyl) (phenyl) amino) -2-hydroxy-2-methylpropanamide (49): Yield; 67%; MS (ESI) m / z 456.1 [M - H]-;1NMR (400 MHz, CDCl3) δ 8.85 (br s, 1H, NH), 7.87 (m, 1H), 7.81-7.73 (m, 2H), 7.65 (dd, J = 8.4, 1, 8 Hz, 1H), 7.20 (m, 2H), 7.05-7.00 (m, 2H), 6.94-6.89 (m, 5H), 4.54 (d, J = 15 , 2 Hz, 1H), 3.84 (d, J = 15.2 Hz, 1H), 3.61 (s, 1H), 1.53 (s, 3H).

Example 2

New AR Antagonists

The purpose of this study is:

Synthesize and optimize the oral bioavailable SARD and derive the structure-activity ratio (SAR).

Characterize SARD in vitro in AR ligand binding, transactivation, and AR degradation and proliferation assays in PCa cells that are dependent on AR-FL and AR-SV for growth.

Determine pharmacokinetic properties (PK), develop an appropriate formulation, and characterize SARD in vivo in LNCaP and androgen-dependent 22RV-1 and CRPC xenografts, respectively.

Preliminary results were obtained using two headed molecules, compounds 17 and 14, selected from the library.

Several molecules have been synthesized and characterized with the intention of developing next-generation AR antagonists. Interestingly, some of these AR antagonists exhibited degradation activity at concentrations comparable to their binding and antagonistic activity. These results gave impetus to the study of the degradation activity of these molecules.

Table 1. SARD of the present invention, binding and antagonistic AR actions

<tables num="1"><table frame="all"><tgroup align="center" rowsep="1" colsep="1" cols="10"><colspec colname="c1" colwidth="23mm" /><colspec colname="c2" colwidth="17mm" /><colspec colname="c3" colwidth="6mm" /><colspec colname="c4" colwidth="12mm" /><colspec colname="c5" colwidth="10mm" /><colspec colname="c6" colwidth="11mm" /><colspec colname="c7" colwidth="11mm" /><colspec colname="c8" colwidth="10mm" /><colspec colname="c9" colwidth="11mm" /><colspec colname="c10" colwidth="21mm" /><tbody><row><entry valign="middle" rowsep="1" colsep="1" /><entry valign="middle" align="center" rowsep="1" colsep="1">X</entry><entry namest="c3" nameend="c4" valign="middle" align="center" rowsep="1" colsep="1">R1</entry><entry namest="c5" nameend="c6" valign="middle" align="center" rowsep="1" colsep="1">R2</entry><entry namest="c7" nameend="c8" valign="middle" align="center" rowsep="1" colsep="1">Ki (nM)</entry></row><row><entry valign="middle" align="center" rowsep="1" colsep="1">DHT</entry><entry valign="middle" align="center" rowsep="1" colsep="1">n / a</entry><entry namest="c3" nameend="c4" valign="middle" align="center" rowsep="1" colsep="1">n / a</entry><entry namest="c5" nameend="c6" valign="middle" align="center" rowsep="1" colsep="1">n / a</entry><entry namest="c7" nameend="c8" valign="middle" align="center" rowsep="1" colsep="1">6. 62</entry></row><row><entry valign="middle" align="center" rowsep="1" colsep="1">MDV-3100</entry><entry valign="middle" align="center" rowsep="1" colsep="1">n / a</entry><entry namest="c3" nameend="c4" valign="middle" align="center" rowsep="1" colsep="1">n / a</entry><entry namest="c5" nameend="c6" valign="middle" align="center" rowsep="1" colsep="1">n / a</entry><entry namest="c7" nameend="c8" valign="middle" align="center" rowsep="1" colsep="1">1075. 3</entry></row><row><entry valign="middle" align="center" rowsep="1" colsep="1">bicalutamide</entry><entry valign="middle" align="center" rowsep="1" colsep="1">SO2</entry><entry namest="c3" nameend="c4" valign="middle" align="center" rowsep="1" colsep="1">F</entry><entry namest="c5" nameend="c6" valign="middle" align="center" rowsep="1" colsep="1">H</entry><entry namest="c7" nameend="c8" valign="middle" align="center" rowsep="1" colsep="1">545. 5</entry></row><row><entry valign="middle" align="center" rowsep="1" colsep="1">Connection 17</entry><entry valign="middle" align="center" rowsep="1" colsep="1">N (CH3)</entry><entry namest="c3" nameend="c4" valign="middle" align="center" rowsep="1" colsep="1">CN</entry><entry namest="c5" nameend="c6" valign="middle" align="center" rowsep="1" colsep="1">Phenyl</entry><entry namest="c7" nameend="c8" valign="middle" align="center" rowsep="1" colsep="1">148. 7</entry></row><row><entry valign="middle" align="center" rowsep="1" colsep="1">Connection fourteen</entry><entry valign="middle" align="center" rowsep="1" colsep="1">NH</entry><entry namest="c3" nameend="c4" valign="middle" align="center" rowsep="1" colsep="1">CN</entry><entry namest="c5" nameend="c6" valign="middle" align="center" rowsep="1" colsep="1">phenyl</entry><entry namest="c7" nameend="c8" valign="middle" align="center" rowsep="1" colsep="1">198. 5</entry></row><row><entry valign="middle" rowsep="1" colsep="0" /><entry valign="middle" rowsep="1" colsep="0" /><entry namest="c3" nameend="c4" valign="middle" rowsep="1" colsep="0" /><entry namest="c5" nameend="c6" valign="middle" rowsep="1" colsep="0" /><entry namest="c7" nameend="c8" valign="middle" rowsep="1" colsep="0" /></row><row><entry valign="middle" rowsep="1" colsep="1" /><entry namest="c2" nameend="c3" valign="middle" rowsep="1" colsep="1" /><entry namest="c4" nameend="c10" valign="middle" align="center" rowsep="1" colsep="0">Transcription activation (antagonist mode)</entry></row><row><entry valign="middle" rowsep="1" colsep="1" /><entry namest="c2" nameend="c3" valign="middle" align="center" rowsep="1" colsep="1">binding</entry><entry namest="c4" nameend="c7" valign="middle" align="center" rowsep="1" colsep="1">Wild type</entry><entry namest="c8" nameend="c10" valign="middle" align="center" rowsep="1" colsep="0">W741l</entry></row><row><entry valign="middle" align="center" rowsep="1" colsep="1">Compound</entry><entry namest="c2" nameend="c3" valign="middle" align="center" rowsep="1" colsep="1">Ki(nM)</entry><entry namest="c4" nameend="c5" valign="middle" align="center" rowsep="1" colsep="1">IC50(nM)</entry><entry namest="c6" nameend="c7" valign="middle" align="center" rowsep="1" colsep="1">% inhibition at 1 μm</entry><entry namest="c8" nameend="c9" valign="middle" align="center" rowsep="1" colsep="1">IC50(nM)</entry><entry valign="middle" align="center" rowsep="1" colsep="0">% inhibition at 1 μM</entry></row><row><entry valign="middle" align="center" rowsep="1" colsep="1">DHT</entry><entry namest="c2" nameend="c3" valign="middle" align="center" rowsep="1" colsep="1">5,85</entry><entry namest="c4" nameend="c5" valign="middle" rowsep="1" colsep="1" /><entry namest="c6" nameend="c7" valign="middle" rowsep="1" colsep="1" /><entry namest="c8" nameend="c9" valign="middle" rowsep="1" colsep="1" /><entry valign="middle" rowsep="1" colsep="0" /></row><row><entry valign="middle" align="center" rowsep="1" colsep="1">bicalutamide</entry><entry namest="c2" nameend="c3" valign="middle" align="center" rowsep="1" colsep="1">545,5</entry><entry namest="c4" nameend="c5" valign="middle" align="center" rowsep="1" colsep="1">420</entry><entry namest="c6" nameend="c7" valign="middle" align="center" rowsep="1" colsep="1">91</entry><entry namest="c8" nameend="c9" valign="middle" align="center" rowsep="1" colsep="1">-</entry><entry valign="middle" align="center" rowsep="1" colsep="0">-</entry></row><row><entry valign="middle" align="center" rowsep="1" colsep="1">MDV-3100</entry><entry namest="c2" nameend="c3" valign="middle" align="center" rowsep="1" colsep="1">10753</entry><entry namest="c4" nameend="c5" valign="middle" align="center" rowsep="1" colsep="1">489</entry><entry namest="c6" nameend="c7" valign="middle" align="center" rowsep="1" colsep="1">93</entry><entry namest="c8" nameend="c9" valign="middle" align="center" rowsep="1" colsep="1">939</entry><entry valign="middle" align="center" rowsep="1" colsep="0">53</entry></row><row><entry valign="middle" align="center" rowsep="1" colsep="1">ARN-509</entry><entry namest="c2" nameend="c3" valign="middle" rowsep="1" colsep="1" /><entry namest="c4" nameend="c5" valign="middle" align="center" rowsep="1" colsep="1">297</entry><entry namest="c6" nameend="c7" valign="middle" rowsep="1" colsep="1" /><entry namest="c8" nameend="c9" valign="middle" align="center" rowsep="1" colsep="1">1939,4</entry><entry valign="middle" rowsep="1" colsep="0" /></row><row><entry valign="middle" align="center" rowsep="1" colsep="1">ASC-J9</entry><entry namest="c2" nameend="c3" valign="middle" rowsep="1" colsep="1" /><entry namest="c4" nameend="c5" valign="middle" align="center" rowsep="1" colsep="1">1008</entry><entry namest="c6" nameend="c7" valign="middle" rowsep="1" colsep="1" /><entry namest="c8" nameend="c9" valign="middle" align="center" rowsep="1" colsep="1">3487,6</entry><entry valign="middle" rowsep="1" colsep="0" /></row><row><entry valign="middle" align="center" rowsep="1" colsep="1">14</entry><entry namest="c2" nameend="c3" valign="middle" align="center" rowsep="1" colsep="1">198,5</entry><entry namest="c4" nameend="c5" valign="middle" align="center" rowsep="1" colsep="1">77</entry><entry namest="c6" nameend="c7" valign="middle" align="center" rowsep="1" colsep="1">92</entry><entry namest="c8" nameend="c9" valign="middle" align="center" rowsep="1" colsep="1">>1000</entry><entry valign="middle" align="center" rowsep="1" colsep="0">48</entry></row><row><entry valign="middle" align="center" rowsep="0" colsep="1">17</entry><entry namest="c2" nameend="c3" valign="middle" align="center" rowsep="0" colsep="1">270,7</entry><entry namest="c4" nameend="c5" valign="middle" align="center" rowsep="0" colsep="1">95</entry><entry namest="c6" nameend="c7" valign="middle" align="center" rowsep="0" colsep="1">98</entry><entry namest="c8" nameend="c9" valign="middle" align="center" rowsep="0" colsep="1">101,7</entry><entry valign="middle" align="center" rowsep="0" colsep="0">87</entry></row></tbody></tgroup></table></tables>

table 2

<tables num="1"><table frame="all"><tgroup rowsep="1" colsep="1" cols="6"><colspec colname="c1" colwidth="29mm" /><colspec colname="c2" colwidth="26mm" /><colspec colname="c3" colwidth="21mm" /><colspec colname="c4" colwidth="21mm" /><colspec colname="c5" colwidth="21mm" /><colspec colname="c6" colwidth="46mm" /><tbody><row><entry valign="middle" rowsep="1" colsep="1" /><entry valign="middle" rowsep="1" colsep="1" /><entry namest="c3" nameend="c5" valign="middle" rowsep="1" colsep="1">Transcription Activation</entry><entry valign="middle" rowsep="1" colsep="0">DMPK (mouse liver microsomes)</entry></row><row><entry valign="middle" rowsep="1" colsep="1" /><entry valign="middle" rowsep="1" colsep="1">binding</entry><entry valign="middle" rowsep="1" colsep="1">Wt.</entry><entry valign="middle" rowsep="1" colsep="1">W741l</entry><entry valign="middle" rowsep="1" colsep="1">T877A</entry><entry valign="middle" rowsep="1" colsep="0" /></row><row><entry valign="middle" rowsep="1" colsep="1">Compound</entry><entry valign="middle" rowsep="1" colsep="1">Ki(nM)</entry><entry valign="middle" rowsep="1" colsep="1">IC50(nM)</entry><entry valign="middle" rowsep="1" colsep="1">IC50(nM)</entry><entry valign="middle" rowsep="1" colsep="1">IC50(nM)</entry><entry valign="middle" rowsep="1" colsep="0">T1/2 (min) CLint(ml / min / kg)</entry></row><row><entry valign="middle" rowsep="1" colsep="1">DHT</entry><entry valign="middle" rowsep="1" colsep="1">1</entry><entry valign="middle" rowsep="1" colsep="1" /><entry valign="middle" rowsep="1" colsep="1" /><entry valign="middle" rowsep="1" colsep="1" /><entry valign="middle" rowsep="1" colsep="0" /></row><row><entry valign="middle" rowsep="1" colsep="1">Bicalutamide</entry><entry valign="middle" rowsep="1" colsep="1">545,5</entry><entry valign="middle" rowsep="1" colsep="1">420</entry><entry valign="middle" rowsep="1" colsep="1">-</entry><entry valign="middle" rowsep="1" colsep="1">557</entry><entry valign="middle" rowsep="1" colsep="0" /></row><row><entry valign="middle" rowsep="1" colsep="1">enzalutamide</entry><entry valign="middle" rowsep="1" colsep="1">1075,3</entry><entry valign="middle" rowsep="1" colsep="1">489</entry><entry valign="middle" rowsep="1" colsep="1">939</entry><entry valign="middle" rowsep="1" colsep="1">331,94</entry><entry valign="middle" rowsep="1" colsep="0" /></row><row><entry valign="middle" rowsep="1" colsep="1">ARN-509</entry><entry valign="middle" rowsep="1" colsep="1" /><entry valign="middle" rowsep="1" colsep="1">297,0</entry><entry valign="middle" rowsep="1" colsep="1">1939,4</entry><entry valign="middle" rowsep="1" colsep="1">390,52</entry><entry valign="middle" rowsep="1" colsep="0" /></row><row><entry valign="middle" rowsep="1" colsep="1">ASC-J9</entry><entry valign="middle" rowsep="1" colsep="1" /><entry valign="middle" rowsep="1" colsep="1">1008</entry><entry valign="middle" rowsep="1" colsep="1">3487,6</entry><entry valign="middle" rowsep="1" colsep="1" /><entry valign="middle" rowsep="1" colsep="0" /></row><row><entry valign="middle" rowsep="1" colsep="1">14</entry><entry valign="middle" rowsep="1" colsep="1">198,5</entry><entry valign="middle" rowsep="1" colsep="1">77</entry><entry valign="middle" rowsep="1" colsep="1">>1000</entry><entry valign="middle" rowsep="1" colsep="1">48</entry><entry valign="middle" rowsep="1" colsep="0">See Example 6</entry></row><row><entry valign="middle" rowsep="1" colsep="1">17</entry><entry valign="middle" rowsep="1" colsep="1">28,4</entry><entry valign="middle" rowsep="1" colsep="1">95</entry><entry valign="middle" rowsep="1" colsep="1">101,7</entry><entry valign="middle" rowsep="1" colsep="1">153,51</entry><entry valign="middle" rowsep="1" colsep="0">See Example 6</entry></row><row><entry valign="middle" rowsep="0" colsep="1">49</entry><entry valign="middle" rowsep="0" colsep="1">275,41</entry><entry valign="middle" rowsep="0" colsep="1">172,22</entry><entry valign="middle" rowsep="0" colsep="1" /><entry valign="middle" rowsep="0" colsep="1" /><entry valign="middle" rowsep="0" colsep="0">5,069 min 136.8 ml / min / mg#</entry></row></tbody></tgroup></table></tables>

# -Cm. MLM way below:

Study of metabolism with mouse liver microsomes (MLM)

Purpose. Determine the relative stability of SARD to the metabolism of microsomal liver enzymes using MLM.

Method: Determination of metabolic stability (in vitro CLint) of test compounds in relation to phase I and phase I + II of the metabolic pathways.

Metabolic stability to phase I pathways: Analysis was performed in a final volume of 0.5 ml in duplicates (n = 2). The test compound (1 μM) was pre-incubated for 10 minutes at 37 ° C in 100 mM Tris-HCl, pH 7.5, containing 0.5 mg / ml liver microsomal protein. After pre-incubation, the reaction was started by adding 1 mM NADPH (pre-incubated at 37 ° C). Incubations were performed in triplicate, and at various time points (0.5, 10, 15, 30, and 60 minutes), 100 μl aliquots were collected and quenched with 100 μl acetonitrile containing an internal standard. Samples were vortexed and centrifuged at 4000 rpm for 10 minutes. Supernatants were transferred to 96-well plates and presented for analysis by LC-MS / MS. Incubation of samples performed in the absence of NADPH was included as a control. From the% PCR (% of the remaining starting compound), the rate of disappearance of the compound (slope) was determined and the in vitro CLint (μl / min / mg protein) was calculated.

Metabolic stability in phase I and phase II pathways. In this assay, the test compound was incubated with liver microsomes and the disappearance of the drug was determined using an LC-MC / MC score for detection. To stimulate the metabolic pathway of Phase II (glucuronidation), UDPGA and alamethicin were included in the analysis.

LC-MS / MS analysis. Analysis of the studied compounds was carried out using an LC-MS / MS system consisting of an Agilent 1100 HPLC with an MDS / Sciex 4000 Q-Trap ™ mass spectrometer. Separation was achieved using an analytical column (AlltimaTM, 2.1 X 100 mm, 3 μm) protected by a protective cartridge system C18 (Security Guard ™ ULTRA HPLC cartridges for 4.6 mm ID columns, Phenomenex). The mobile phase consisted of channel A (95% acetonitrile + 5% water + 0.1% formic acid) and channel C (95% water + 5% acetonitrile + 0.1% formic acid) and was supplied at a flow rate of 0.4 ml / min The volume ratio of acetonitrile and water is optimized for each of the analytes. Multiple reaction monitoring (mRM) scans were performed using a gas curtain, collision gas, a gas atomizer, and auxiliary gas optimized for each compound and source temperature at 550 ° C. Molecular ions were formed using an ion sputtering voltage (IS) of -4200 V (negative mode). For each compound, splitting potential (DP), input potential (EP), collision energy (CE), product ion mass and cell yield potential (CXP) were optimized.

As shown in Table 1, first generation SARDs were obtained with amino linkers. Their binding and AR antagonistic activities were compared with standard molecules such as bicalutamide, enzalutamide (MDV3100), ARN-509 and ASC-J9.

As shown in Table 1 and Table 2, the SARDs of the invention bind to AR with higher affinity than reference standards. It is interesting to note that the two molecules from the list, compounds 14 and 17, are tightly bound to AR by displacing the radioisotope labeled miboleron from LBD in an AR-LBD binding assay. They are associated with much higher affinities than reference standards. In accordance with strong binding, the two molecules effectively antagonized R1881 stimulated activity of wild-type AR transcription with an efficiency of at least five times that of MDV-3100 and bicalutamide (77 nM and 95 nM for 14 and 17, respectively, compared to 420 nM and 489 nM for bicalutamide and MDV-3100, respectively) (table 1 and table 2).

Bicalutamide is a known AR agonist containing the W741L mutation, while MDV-3100 retains the activity of the antagonist, although its activity is slightly reduced (939 nM). While 14 showed a decrease in the efficiency of the W741L mutant (> 1 μM), 17 retained the ability to antagonize the activated W741LAR agonist (101. 7 nM). The W741L mutation was selected due to the structural similarity of SARD with bicalutamide (arylpropanamide). Antagonistic activity 17 was selective for AR and did not cross-react with progesterone receptor (PR), minerocorticoid receptor (MR) or glucocorticoid receptors (GR) ( data not shown).

In general, compounds 12-21 act as antagonists of the wild type androgen receptor (wt-AR) with some residual agonism for 12, 13 and 15. It is noteworthy that 17 was the most potent antagonist with an IC value50 6 nM (table 3). The mutant ARW741L and T877A are resistant to bicalutamide and hydroxyflutamide, respectively. Most compounds 12-21 showed a mixed agonist / antagonist activity in in vitro transcription activation assays. However, 17 retains strong pure wild-type antagonism and both mutations (Table 3 and Table 4), demonstrating the potential to overcome resistance to bicalutamide and / or hydroxyflutamide, regardless of its SARD activity (described below). fourteen also demonstrated the activity of wild type and mutant AR antagonists, but was not a potent antagonist in all tested mutants.

Example 3

AR degradation activity

Compounds 17 and 14 were tested for their effect on the expression of the AP protein. While 17 dramatically decreased AR protein levels after 24 hours of treatment in LNCaP cells (serum depleted and treated with 0.1 nM R1881) as measured by western blotting (Figure 1A), bicalutamide or enzalutamide (MDV-3100) did not no effect on (Figure 1E (VCaP) and 1F (LNCaP)). Under the same conditions, the lowest concentration of 17, which is able to lower AR protein levels in LNCaP cells, was 100 nM (Figure 1B). A similar suppression of AR protein was observed under conditions of hormone overflow in LNCaP (Figure 1C), in HeLa cells infected with adenovirus expressing high levels of wt-AR (Figure 1D, suggesting activity in CPRC, where the AR gene is activated), as well as in wt-AR expressing VCaP cells 14 (figure 1E). fourteen also similarly reduced AR levels in LNCaP cells, requiring only 2 hours of treatment and closely matching 17-AAG time (Figure 1F). Neither bicalutamide nor MDV-3100 (enzalutamide) exerted any effect on AR protein levels even after 24 hours of treatment. Similarly, 17 demonstrated stronger and more complete degradation of AR in LNCaP cells than those described by SARDASC-J9 (not shown) and ARN-509 (Figure 2A), and an AR antagonist enzalutamide (not shown) (Figure 2A). 17 and 14 in LNCaP cells resulted in a slight decrease in AR mRNA levels, but only at 10 μM, and not at 1 μM. Unlike the HSP-90 17-AAG inhibitor, treatment17 did not affect PR (Figure 4E), GR (not shown) and ERα (Figure 4F) protein levels (Figure 4).

Figure 9 shows that 49 in the presence of R1881 degrades AR in LNCaP cells. LNCaP cells were seeded in 6-well plates at 1 million cells / well. Cells were kept under serum-free conditions for 3 days. Cells were processed as indicated in the figure, collected, the protein was extracted and Western blotting was performed for AR. 49 and other SARDs of the present invention demonstrated selective AR degradation (i.e., SARD activity) in the nM range, i.e., in concentrations comparable to their IC values50 antagonist. LNCaP cells are known to express the T877A AR mutant, demonstrating the ability to degrade the antiandrogen resistance giving mutant androgen receptors.

Figure 10 shows that 49 degrades AR in RV22-1 cells. 22RV-1 cells were seeded in a 6-well plate at 1-1.5 million cells / well in growth medium (RPMI + 10% FBS). The next day, the medium was changed and treated with a carrier medium or a dose response of 49. After overnight treatment (12-16 hours), the cells were washed in ice-cold PBS and collected by separation in 1 ml of PBS. The cells were granulated, the protein was extracted, quantified using BCA analysis, and an equal amount of protein was fractionated on SDS-PAGE. Proteins were transferred onto a nylon membrane and Western blotted with an AR antibody (N20 from SCBT) and an actin antibody. 49 was able to degrade the androgen receptor full length (AR-FL) and cropped AR (AR-SV) in 22RV-1 cells, which indicates that SARDs will be able to overcome prostate cancer-dependent AR-V7 diseases.

LNCaP cells are known to express the T877A AR mutant, demonstrating the ability of the SARD of the present invention to degrade antiandrogen resistance giving mutant androgen receptors (i.e. progressive prostate cancer and CRPC). 14, 17, and 49 are capable of degrading the full length androgen receptor (AR-FL) and cropped AR (AR-SV) in 22RV-1 cells, indicating that SARDs will be able to overcome prostate cancer-dependent AR-V7 diseases ( have a CRPC).

These demonstrations of SARD activity show that the compounds of the present invention are capable of degrading various variants of AR and, therefore, should provide the ability to inhibit the activity of the AR axis, regardless of whether it is androgen-dependent or androgen-independent. AR degradation eliminates the possibility of random activation of mutant ARs, activation by intracellular processes such as signal transduction and kinase activation, etc .; and suggests that SARDs should also destroy polyQ polymorphisms in hyperandrogenic dermatological disorders (abbreviated polyQ) or Kennedy's disease (expanded polyQ), providing the rationale for treating any type of disease by destroying AR in affected tissues (skin and neuromuscular system, respectively).

Example 4

Effect on PCa Gene Expression and Cell Growth

The ability of these new antagonists to inhibit expression regulated by AR was measured in the LNCaP of the PCa cell line known as the T877A mutation (Table 5).

Table 5. The effect of antagonists on the AR target of gene expression and growth in LNCaP cells

<tables num="1"><table frame="all"><tgroup rowsep="1" colsep="1" cols="4"><colspec colname="c1" colwidth="42mm" /><colspec colname="c2" colwidth="42mm" /><colspec colname="c3" colwidth="42mm" /><colspec colname="c4" colwidth="42mm" /><tbody><row><entry morerows="1" valign="middle" rowsep="1" colsep="1">Gene</entry><entry namest="c2" nameend="c4" valign="middle" rowsep="1" colsep="0">Gene expression + 0.1 nMR 1881 (IC50nM)</entry></row><row><entry valign="middle" align="center" rowsep="1" colsep="1">Bicalutamide</entry><entry valign="middle" align="center" rowsep="1" colsep="1">MDV-3100</entry><entry valign="middle" align="center" rowsep="1" colsep="0">Connection 17</entry></row><row><entry valign="middle" rowsep="1" colsep="1">PSA</entry><entry valign="middle" align="center" rowsep="1" colsep="1">783,7</entry><entry valign="middle" align="center" rowsep="1" colsep="1">1, 019,3</entry><entry valign="middle" align="center" rowsep="1" colsep="0">198,5</entry></row><row><entry valign="middle" rowsep="1" colsep="1">NKx3.1</entry><entry valign="middle" align="center" rowsep="1" colsep="1">755,8</entry><entry valign="middle" align="center" rowsep="1" colsep="1">1, 142,8</entry><entry valign="middle" align="center" rowsep="1" colsep="0">176,0</entry></row><row><entry valign="middle" rowsep="1" colsep="1">FKBP51</entry><entry valign="middle" align="center" rowsep="1" colsep="1">270,9</entry><entry valign="middle" align="center" rowsep="1" colsep="1">76,8</entry><entry valign="middle" align="center" rowsep="1" colsep="0">51,8</entry></row><row><entry valign="middle" rowsep="1" colsep="1">TMPRSS2</entry><entry valign="middle" align="center" rowsep="1" colsep="1">831,4</entry><entry valign="middle" align="center" rowsep="1" colsep="1">823,7</entry><entry valign="middle" align="center" rowsep="1" colsep="0">128,1</entry></row><row><entry valign="middle" rowsep="0" colsep="1">growth</entry><entry valign="middle" rowsep="0" colsep="1" /><entry valign="middle" align="center" rowsep="0" colsep="1">872</entry><entry valign="middle" align="center" rowsep="0" colsep="0">469</entry></row></tbody></tgroup></table></tables>

According to binding and transcription activation assays, 17 significantly inhibited agonist-stimulated expression of the PSA, NKx3,1, FKBP51 and TMPRSS2 genes (IC values50 198.5, 176.0, 51.8 and 128.1 nM, respectively).

Table 6

<tables num="1"><table frame="all"><tgroup align="center" rowsep="1" colsep="1" cols="13"><colspec colname="c1" colwidth="16mm" /><colspec colname="c2" colwidth="13mm" /><colspec colname="c3" colwidth="8mm" /><colspec colname="c4" colwidth="11mm" /><colspec colname="c5" colwidth="13mm" /><colspec colname="c6" colwidth="16mm" /><colspec colname="c7" colwidth="13mm" /><colspec colname="c8" colwidth="13mm" /><colspec colname="c9" colwidth="13mm" /><colspec colname="c10" colwidth="17mm" /><colspec colname="c11" colwidth="11mm" /><colspec colname="c12" colwidth="11mm" /><colspec colname="c13" colwidth="18mm" /><tbody><row><entry morerows="1" valign="middle" rowsep="1" colsep="1">Cell line / R1881</entry><entry namest="c2" nameend="c5" valign="middle" rowsep="1" colsep="1">Connection 17 7days growth (IC50, μm)</entry><entry namest="c6" nameend="c9" valign="middle" rowsep="1" colsep="1">17-AAG 7 days growth (IC50, μm)</entry><entry namest="c10" nameend="c13" valign="middle" rowsep="1" colsep="0">Ansalutamide 7days growth (IC50, μm)</entry></row><row><entry valign="middle" align="center" rowsep="1" colsep="1">Veh</entry><entry valign="middle" align="center" rowsep="1" colsep="1">0,01</entry><entry valign="middle" align="center" rowsep="1" colsep="1">0,1</entry><entry valign="middle" align="center" rowsep="1" colsep="1">10</entry><entry valign="middle" align="center" rowsep="1" colsep="1">Veh</entry><entry valign="middle" align="center" rowsep="1" colsep="1">0,01</entry><entry valign="middle" align="center" rowsep="1" colsep="1">0,1</entry><entry valign="middle" align="center" rowsep="1" colsep="1">10</entry><entry valign="middle" align="center" rowsep="1" colsep="1">Veh</entry><entry valign="middle" align="center" rowsep="1" colsep="1">0,01</entry><entry valign="middle" align="center" rowsep="1" colsep="1">0,1</entry><entry valign="middle" align="center" rowsep="1" colsep="0">10</entry></row><row><entry valign="middle" rowsep="1" colsep="1">VcaP</entry><entry valign="middle" align="center" rowsep="1" colsep="1">2. 99</entry><entry valign="middle" align="center" rowsep="1" colsep="1">2,92</entry><entry valign="middle" align="center" rowsep="1" colsep="1">2,48</entry><entry valign="middle" align="center" rowsep="1" colsep="1">3,82</entry><entry valign="middle" align="center" rowsep="1" colsep="1">0,657</entry><entry valign="middle" align="center" rowsep="1" colsep="1">0,414</entry><entry valign="middle" align="center" rowsep="1" colsep="1">0,778</entry><entry valign="middle" align="center" rowsep="1" colsep="1">1,06</entry><entry valign="middle" align="center" rowsep="1" colsep="1">0,742</entry><entry valign="middle" align="center" rowsep="1" colsep="1">1,53</entry><entry valign="middle" align="center" rowsep="1" colsep="1">>3</entry><entry valign="middle" align="center" rowsep="1" colsep="0">>10</entry></row><row><entry valign="middle" rowsep="1" colsep="1">LNCaP</entry><entry valign="middle" align="center" rowsep="1" colsep="1">0. 78</entry><entry valign="middle" align="center" rowsep="1" colsep="1">0,49</entry><entry valign="middle" align="center" rowsep="1" colsep="1">0,47</entry><entry valign="middle" align="center" rowsep="1" colsep="1">--</entry><entry valign="middle" align="center" rowsep="1" colsep="1">0,260</entry><entry valign="middle" align="center" rowsep="1" colsep="1">0,292</entry><entry valign="middle" align="center" rowsep="1" colsep="1">0,157</entry><entry valign="middle" align="center" rowsep="1" colsep="1">-</entry><entry valign="middle" align="center" rowsep="1" colsep="1">0,281</entry><entry valign="middle" align="center" rowsep="1" colsep="1">0,656</entry><entry valign="middle" align="center" rowsep="1" colsep="1">3,02</entry><entry valign="middle" align="center" rowsep="1" colsep="0">-</entry></row><row><entry valign="middle" rowsep="0" colsep="1">PC-3</entry><entry valign="middle" align="center" rowsep="0" colsep="1">>10</entry><entry valign="middle" align="center" rowsep="0" colsep="1">>10</entry><entry valign="middle" align="center" rowsep="0" colsep="1">>10</entry><entry valign="middle" align="center" rowsep="0" colsep="1">>10</entry><entry valign="middle" align="center" rowsep="0" colsep="1">0,307</entry><entry valign="middle" align="center" rowsep="0" colsep="1">0,221</entry><entry valign="middle" align="center" rowsep="0" colsep="1">0,257</entry><entry valign="middle" align="center" rowsep="0" colsep="1">0,542</entry><entry valign="middle" align="center" rowsep="0" colsep="1">>10</entry><entry valign="middle" align="center" rowsep="0" colsep="1">>10</entry><entry valign="middle" align="center" rowsep="0" colsep="1">>10</entry><entry valign="middle" align="center" rowsep="0" colsep="0">>10</entry></row></tbody></tgroup></table></tables>

Similar activity was demonstrated in LNCaP cells with 14 (not shown). In accordance with the inhibition of gene expression, 17 inhibited the growth of AR-positive, androgen-dependent PCa cells (LNCaP and VCaP) in both hormone-depleted and hormone-specific states (Table 6). Unlike the HSP-90 inhibitor 17-AAG, 17 did not affect the negative cell line of PC, PC-3 (table 6). Cm. also Figure 2B for a histogram showing that 17 inhibits LNCaP cell growth with comparable efficacy and action like enzalutamide and ARN-509.

Example 5

SARD degradation of AR-SV in 22RV-1 cells.

The efficacy of SARD treatment for AR levels was also measured in androgen-refractory 22RV-1 PCa cells. These cells express both AR-FL and AR low molecular weight hybrid splicing variants (AR-SV), and are dependent on AR-SV for growth. 17 (figures 3A and 3B) and 14 (figure 3C) are fully adjusted by both AR-FL and AR-SV (figure 3), in contrast to the limited effects of 17-AAG only on AR-FL (not shown). Treatment with MDV-3100 did not affect the levels of both types of AR (Figure 3C), while ASC-J9 and ARN-509 did not reduce levels of AR-V7. Growth analysis performed on 22RV-1 cells treated with SARD in the presence or absence of 0.1 nM R1881 showed that SARD, but not MDV-3100, bicalutamide, enzalutamide or ARN-509, markedly inhibits the growth of 22RV-1 cells ( table 7). AR-SV variant (e.g. AR-V7; CancerRes. 2013 Jan 15; 73 (2): 483-489) does not have LBD, and therefore SARD activity against AR-SV should work through an alternative binding and degradation domain (BDD).

Table 7. The effect of SARD on transactivation of AR and growth in 22RV-1 cells.

<tables num="1"><table frame="all"><tgroup rowsep="1" colsep="1" cols="3"><colspec colname="c1" colwidth="42mm" /><colspec colname="c2" colwidth="38mm" /><colspec colname="c3" colwidth="32mm" /><tbody><row><entry rowsep="1" colsep="1" /><entry align="center" rowsep="1" colsep="1">Transactivation</entry><entry align="center" rowsep="1" colsep="0">Growth</entry></row><row><entry rowsep="1" colsep="1">Compound</entry><entry align="center" rowsep="1" colsep="1">IC50 (nM)</entry><entry align="center" rowsep="1" colsep="0">IC50 (nM)</entry></row><row><entry rowsep="1" colsep="1">Bicalutamide</entry><entry align="center" rowsep="1" colsep="1">3133,52</entry><entry align="center" rowsep="1" colsep="0">>10,000</entry></row><row><entry rowsep="1" colsep="1">Anzalutamide</entry><entry align="center" rowsep="1" colsep="1">101,87</entry><entry align="center" rowsep="1" colsep="0">>10,000</entry></row><row><entry rowsep="1" colsep="1">Connection 17</entry><entry align="center" rowsep="1" colsep="1">56,36</entry><entry align="center" rowsep="1" colsep="0">2642</entry></row><row><entry rowsep="1" colsep="1">ARN-509</entry><entry align="center" rowsep="1" colsep="1">64,54</entry><entry align="center" rowsep="1" colsep="0">>10,000</entry></row><row><entry rowsep="0" colsep="1">ASC-J9</entry><entry align="center" rowsep="0" colsep="1">1026,91</entry><entry align="center" rowsep="0" colsep="0">>10, 000</entry></row></tbody></tgroup></table></tables>

Figure 4 shows the degradation of AR by SARD under various conditions (AD), without destroying other receptors (EF). (A.) and (B.). LNCaP cells were serum-free and treated with compound 17 (10 μM in panel A and dose response in panel B) in the presence or absence of R1881. Bicalutamide was used as a negative control. Cells were harvested, the protein was extracted, and Western blotting was performed for AR and actin. (C.) LNCaP cells were seeded in pure serum and treated with compound 17 (dose response). Cells were harvested, the protein was extracted, and Western blotting was performed for AR and actin. (D.) HeLa cells were infected with an adenovirus containing AP and treated with compound 17 in the presence or absence of R1881. Cells were harvested, the protein was extracted, and Western blotting was performed for AR and actin. (E.) and (F.) SARD do not degrade other nuclear receptors. T47D cells (left panel) and MCF-7 (right panel) were seeded in pure serum and treated with compound 17 (dose response). Cells were harvested, the protein was extracted and Western blotting was performed for PR (progesterone receptor) or ER-α (estrogen-alpha receptor) and actin.

Example 6

Liver Metabolism and Pharmacokinetic (PK) Properties of SARD

To evaluate metabolic stability parameters, such as elimination half-life and clearance, human, rat and dog microsomes were incubated from 17 and 14 for 60 minutes. Both molecules had very short half-lives between 5 and 10 minutes and high clearance (Table 8).

Table 8. DMPK studies with SARD of the invention.

<tables num="1"><table frame="all"><tgroup align="center" rowsep="1" colsep="1" cols="8"><colspec colname="c1" colwidth="15mm" /><colspec colname="c2" colwidth="24mm" /><colspec colname="c3" colwidth="18mm" /><colspec colname="c4" colwidth="16mm" /><colspec colname="c5" colwidth="26mm" /><colspec colname="c6" colwidth="27mm" /><colspec colname="c7" colwidth="24mm" /><colspec colname="c8" colwidth="27mm" /><tbody><row><entry morerows="1" valign="middle" rowsep="1" colsep="1">Sard</entry><entry namest="c2" nameend="c4" valign="middle" align="center" rowsep="1" colsep="1">Rat PK</entry><entry valign="middle" align="center" rowsep="1" colsep="1">RatLM - P1 elimination half-life (min)</entry><entry valign="middle" align="center" rowsep="1" colsep="1">Rat LM - P1 CL (μl / min / mg)</entry><entry valign="middle" align="center" rowsep="1" colsep="1">RatLM - P1 elimination half-life (min)</entry><entry valign="middle" align="center" rowsep="1" colsep="0">Rat LM - P1 CL (μl / min / mg)</entry></row><row><entry valign="middle" align="center" rowsep="1" colsep="1">CL_obs (ml / min / kg)</entry><entry valign="middle" align="center" rowsep="1" colsep="1">IV AUC all (min * mcg / ml)</entry><entry valign="middle" align="center" rowsep="1" colsep="1">PO_F%</entry><entry valign="middle" rowsep="1" colsep="1" /><entry valign="middle" rowsep="1" colsep="1" /><entry valign="middle" rowsep="1" colsep="1" /><entry valign="middle" rowsep="1" colsep="0" /></row><row><entry valign="middle" rowsep="1" colsep="1">17</entry><entry valign="middle" align="center" rowsep="1" colsep="1">30,4</entry><entry valign="middle" align="center" rowsep="1" colsep="1">323,4</entry><entry valign="middle" align="center" rowsep="1" colsep="1">0,7</entry><entry valign="middle" align="center" rowsep="1" colsep="1">4,6</entry><entry valign="middle" align="center" rowsep="1" colsep="1">150,9</entry><entry valign="middle" align="center" rowsep="1" colsep="1">2,5</entry><entry valign="middle" align="center" rowsep="1" colsep="0">281,4</entry></row><row><entry valign="middle" rowsep="0" colsep="1">14</entry><entry valign="middle" align="center" rowsep="0" colsep="1">9,4</entry><entry valign="middle" align="center" rowsep="0" colsep="1">1067,9</entry><entry valign="middle" align="center" rowsep="0" colsep="1">0,4</entry><entry valign="middle" align="center" rowsep="0" colsep="1">7,0</entry><entry valign="middle" align="center" rowsep="0" colsep="1">99,5</entry><entry valign="middle" align="center" rowsep="0" colsep="1">2,6</entry><entry valign="middle" align="center" rowsep="0" colsep="0">266,0</entry></row></tbody></tgroup></table></tables>

The metabolism data of PK studies in rats also showed that SARDs have very low bioavailability and area under the curve (AUC) (Table 8), which indicates that their PK properties need to be improved with structural modifications and an optimal formulation for systemic effects necessary for oral administration and efficacy, for example, for prostate cancer. However, the high potency and effectiveness of degradation of the selective androgen receptor in combination with a low half-life and high metabolic clearance indicate that topical administration of the compounds of the present invention can have strong (high potency and high potency) antiandrogenic effects when applied topically to directly affected areas. For example, local injection into localized skin lesions, such as acne, seborrheic dermatitis, excessive hair growth, etc., can destroy the AR in these tissues, thereby counteracting hyperandrogenism without the risk of significant systemic effects, which can lead to adverse anti-anabolic or sexual side effects. the consequences.

Example 7

Effect on androgen-dependent tissues in intact male rats

To measure in vivo antagonist activity, 17 and 14 were administered to intact male rats by intravenous (iv) bolus injection (Figure 5). Due to the high clearance, studies with the oral administration of these molecules did not have a significant effect on any androgen-dependent tissues, such as the prostate gland, seminal vesicles or levatoris. Therefore, the study was conducted with iv to obtain evidence of in vivo activity. After 3 days of therapy, a decrease in prostate weight, normalized to body weight, was observed in 1 of 2 treated 17 animals and 3 of 4 treated 14 animals compared to control treated carrier medium. The reduction of a larger value in the mass of the seminal vesicle was observed in 4 of 4 animals receiving 14 unchanged in 17 animals. Both test compounds differed greatly in exposure after 23 μF of 14 and 23 μP of 17 doses, resulting in an exposure of 32 and 13 μM * h, respectively. These studies indicate a need for molecules with better bioavailability or a drug that increase oral bioavailability and effectiveness to achieve systemic antiandrogenic effects.

Example 8

SARDs do not inhibit transactivation of other receptors

HEK-293 cells were transfected with the indicated receptors and GRE-LUC and CMV-renillus. Cells were treated 24 hours after transfection and luciferase analysis was performed 48 hours after transfection. SARDs did not inhibit the transactivation of other receptors up to 10 μM (Figure 6).

Example 9

SARD inhibits the recruitment of AR to the promoter and enhancer elements of genes sensitive to androgens

LNCaP cells were serum bleached for 3 days and treated as described above with SARD (compound 17) or bicalutamide at 10 μM in the presence or absence of 0.1 nM R1881. Proteins were crosslinked with DNA, and chromatin immunoprecipitation studies were performed with AR and RNA-PolII antibodies. 17 inhibited recruitment to the promoter or enhancer regions of androgen-sensitive genes such as PSA, FKBP and TMPRSS2 (Figure 7A). SARD degrade AR. LNCaP cells were serum bleached for 3 days and treated as described above with SARD (17) at 10 μM in the presence or absence of 0.1 nM R1881. Cells were fixed and immunofluorescence was performed for AR. The nucleus was stained with DAPI. SARD did not cancel the translocation of AR to the nucleus, but reduced the levels of AR in the nucleus after treatment with the R1881 agonist (Figure 7B).

Example 10

SARD inhibited LNCaP cell growth by non-competitive binding to AR

LNCaP cells were seeded in serum-free medium and treated with an increase in enzalutamide concentration or 17 in the presence of a dose range of R1881. Seven days after treatment, the cells were fixed and growth was measured using a WST-1 assay. SARDs inhibited LNCaP cell growth due to seemingly non-competitive binding to AR (Figure 8). As expected, IC values50 enzalutamide to inhibit cell growth increased with increasing amounts of R1881. However IC values50 to inhibit cell growth for 17 did not increase with the amount of R1881, possibly indicating that R1881 and 17 did not compete for the same AR binding site.

Example 11

Link SARD to AR-AF1

In AF1 AR, there are two tryptophan residues and up to 12 tyrosine residues. This made it possible to study the flexion properties of this region using the fluorescence spectra of the internal steady state. Excitation at 287 nm excites tyrosine and tryptophan residues. Maximum radiation (λmax) for tryptophan is sensitive to solvent. In the presence of the natural osmolyte TMAO, there is a characteristic “blue shift”, which is consistent with tryptophan residues, which are less susceptible to solvent, and shoulder loss (~ 307 nm) for tyrosine, since there is an increase in the energy transfer to tryptophan in the form of folds of polypeptides. To check whether the compounds interact, enobosarm (negative control) and 17 with AF-1 and / or change the bending of this domain, the stationary fluorescence for each compound was measured only with AR-AF1 or the presence of TMAO (3 M) or urea (4 or 6 M). Prior to measuring the emission spectra, 1 μM AR-AF1 and 5 μM individual compounds were preincubated for at least 30 minutes. Emission spectra were adjusted only for the buffer or buffer with TMAO / urea / compounds as necessary.

Figure 11 depicts that the SARD binds to AR-AF1. Figure 11A: All emission spectra were adjusted only for the buffer or buffer with TMAO / urea / compounds as necessary. There was no dramatic effect of enobosarm (left panel) on λmax for tryptophan, and 17 (right panel) reduces the wavelength (ie, “Blue shift”), which indicates that 17 binds to AF-1, and the enobosarm does not bind to AF-1. Figure 11B: Left panel: dose-dependent fluorescence intensity shift, i.e. fluorescence attenuation, for 17 when incubated with ARAF-1. The fluorescence arm observed at 307 nm, which corresponds to the tyrosine residues in AF-1, shifts for 17. The total fluorescence also changes markedly for 17.

Right panel: the data shown in the left panel were displayed as the difference in fluorescence between the control samples and those treated with compound 17 (fluorescence in the absence of compound - fluorescence in the presence of compound). A dose-dependent increase was observed in the presence of 17, indicating an interaction between 17 and AF1.

Example 12

AF1 binding - external validation (VIB)

Target molecule:

Compound 17 was delivered dissolved in DMSO with 10 μM.

Experimental setup

Purified H6-AF1 was biotinylated with N-hydroxysuccinimide (NHS) -PEG4-biotin in an estimated 1: 1 ratio of protein to biotinylation. Biolayer interferometry (BLI) was used to screen the binding of a small molecule to a biotinylated protein using the Octet 96RED system (FortéBio®). Biotinylated H6-AF1 was immobilized on full saturation superstreptavidin (SSA) biosensors to detect signals from small molecule binding. The biosensors loaded with AF1 were used parallel to the screen for binding 17.

results

The raw data measurements from the binding of compound 17 to AF1 are shown in Figure 12. The data show that the loaded AF1 biosensors gave a stronger signal than any of the reference sensors at 50 nM concentrations. At higher concentrations, measurements were not possible due to the solubility problem with the compound.

Although some features of the invention have been illustrated and described in this document, many modifications, substitutions, changes and equivalents will now take place for specialists in this field of technology. Therefore, it should be understood that the appended claims cover all such modifications and changes that fall within the true meaning of the invention.

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US2023041951A1	United States of America	A1	2023-02-09
CN107709290B	China	B	2023-02-28

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Selective androgen receptor destroying agents (sard) and methods of using thereof

Abstract

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SUMMARY OF THE INVENTION

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Priority claims14

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