TWI382837B - Treating muscle wasting with selective androgen receptor modulators - Google Patents

Description

Treatment of muscle loss with selective androgen receptor modulator

The present invention relates to the prevention and treatment of muscle wasting. More specifically, the present invention relates to a method for treating, preventing, suppressing, inhibiting or reducing muscle wasting in a patient suffering from muscle wasting, which is administered to a patient-selective androgen receptor modulator (SARM) compound and/or Analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, or any combination thereof.

Muscle depletion means sustained loss of muscle mass and/or sustained weakening and degeneration of muscles, including skeletal or voluntary muscles that control exercise; myocardial (cardiomyopathy) and smooth muscles that control the heart. Chronic muscle loss is a chronic condition characterized by persistent loss of muscle mass, weakening and degeneration of muscles (ie, lasting for a long time).

The sustained loss of muscle mass during muscle depletion is characterized by the degradation of muscle protein caused by foreignization. Protein catabolism occurs due to very high rates of protein degradation, very low rates of protein synthesis, or a combination of both. Mutagenesis of muscle proteins, whether due to high levels of protein degradation or low protein synthesis, can result in reduced muscle mass and muscle loss.

Muscle depletion is associated with chronic, neurological, hereditary or infectious pathologies, diseases, illnesses or conditions. These include muscular dystrophy, such as Duchenne muscular dystrophy and myotonic dystrophy; muscular dystrophy, muscle atrophy such as post-epidemic polio (PPMA), such as myocardial cachexia, AIDS cachexia and cancer cachexia Cachexia, malnutrition, leprosy, diabetes, kidney disease, chronic obstructive pulmonary disease (COPD), cancer, end stage renal failure, poor muscle disease, emphysema, rickets, HIV infection, AIDS and cardiomyopathy.

In addition, other environments may be related to the condition and cause muscle loss. These include chronic lower back pain, advanced age, central nervous system (CNS) injury, peripheral nerve injury, spinal injury, chemical injury, central nervous system (CNS) damage, peripheral nerve damage, spinal damage, chemical damage, burns, and limbs. Degradation of disuse, long-term hospitalization due to illness or injury and alcoholism.

The complete androgen receptor (AR) signaling pathway is important for proper development of skeletal muscle. Moreover, the complete AR-signaling pathway increases lean meat quality, muscle strength and muscle protein synthesis.

Muscle loss can have horrible consequences if not relieved. For example, changes in the process of muscle depletion can cause weakened physiological conditions that are harmful to personal health, and are prone to cause incomplete fractures and poor physiological performance. In addition, muscle depletion is a strong warning of morbidity and mortality for patients with cachexia and AIDS. In order to prevent and treat muscle loss, especially for chronic muscle loss, innovative methods are urgently needed at the basic science or clinical level. The present invention is to meet these needs.

The present invention provides: (1) a method for treating a patient's muscle wasting, (2) a method for preventing a patient's muscle wasting, and (3) a method for treating, preventing, suppressing, suppressing or reducing muscle loss in a patient suffering from muscle wasting. (4) A method for treating, preventing, inhibiting, reducing, or suppressing muscle wasting in a patient suffering from muscle wasting, and/or (5) a method for treating, preventing, inhibiting, reducing, or suppressing muscle protein dissimilation in a patient suffering from muscle wasting Method for administering a patient-selective androgen receptor modulator (SARM) and/or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxidation Or any combination thereof.

Accordingly, in one embodiment, the invention provides a method of treating a patient's muscle wasting comprising administering to a patient a selective androgen receptor modulator (SARM) compound and/or an analogue, derivative, or isomer thereof , a metabolite, a pharmaceutically acceptable salt, a pharmaceutical product, a hydrate, an N-oxide, or any combination thereof.

In another embodiment, the invention provides a method of preventing muscle wasting in a patient comprising administering to a patient a selective androgen receptor modulator (SARM) compound and/or analogues, derivatives, isomers thereof, The step of a metabolite, a pharmaceutically acceptable salt, a pharmaceutical product, a hydrate, an N-oxide, or any combination thereof.

In another embodiment, the invention provides a method of treating, preventing, suppressing, inhibiting, or reducing muscle loss in a patient suffering from muscle wasting, comprising administering to a patient a selective androgen receptor modulator (SARM) compound and/or The step of an analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide or any combination thereof.

In another embodiment, the invention provides a method of treating, preventing, inhibiting, reducing, or suppressing muscle wasting in a patient suffering from muscle wasting, comprising administering to a patient a selective androgen receptor modulator (SARM) compound and/or The step of an analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide or any combination thereof.

In another embodiment, the invention provides a method of treating, preventing, inhibiting, reducing, or suppressing muscle protein foreignization in a patient suffering from muscle wasting, comprising administering a selective androgen receptor modulator (SARM) compound to a patient The step of / or an analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide or any combination thereof.

In a specific embodiment, it can effectively (1) treat muscle wasting, (2) prevent muscle wasting, (3) treat, prevent, suppress, inhibit or reduce muscle loss caused by muscle wasting, (4) Treat, prevent, inhibit, reduce or suppress muscle loss due to muscle wasting, and/or (5) treat, prevent, inhibit, reduce or suppress SARM compound system due to muscle protein dissimilation caused by muscle wasting Compound of I:

Wherein G is O or S, X is a bond, O, CH ₂ , NH, Se, PR, NO or NR; T is OH, OR, -NHCOCH ₃ or NHCOR; Z is NO ₂ , CN, COOH, COR, NHCOR or CONHR; Y is CF ₃ , F, I, Br, Cl, CN, CR ₃ or SnR ₃ ; Q is alkyl, halogen, CF ₃ , CN, CR ₃ , SnR ₃ , NR ₂ , NHCOCH ₃ , NHCOCF ₃ , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH ₃ , NHCSCF ₃ , NHCSR, NHSO ₂ CH ₃ , NHSO ₂ R, OR, COR, OCOR, OSO ₂ R, SO ₂ R, SR, or Q plus A fused ring system in which the attached benzene ring forms a structure of A, B or C:

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CF ₃ , aryl, phenyl, halogen, alkenyl or OH, and R ₁ Is CH ₃ , CH ₂ F, CHF ₂ , CF ₃ , CH ₂ CH ₃ or CF ₂ CF ₃ .

In another specific embodiment, it can effectively (1) treat muscle wasting, (2) prevent muscle wasting, and (3) treat, prevent, suppress, inhibit or reduce muscle loss caused by muscle wasting, (4) Treating, preventing, inhibiting, reducing or suppressing muscle loss due to muscle wasting, and/or (5) treating, preventing, inhibiting, reducing or suppressing SARM compound system due to muscle protein dissimilation caused by muscle wasting Compound of formula II:

Wherein X is one _{bond, O, CH 2, NH,} Se, PR, NO or NR; Z is _{NO 2, CN, COOH, COR} , NHCOR or CONHR; Y is _{CF 3, F, I, Br} , Cl, CN , CR ₃ or SnR ₃ ; Q is alkyl, halogen, CF ₃ , CN, CR ₃ , SnR ₃ , NR ₂ , NHCOCH ₃ , NHCOCF ₃ , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH ₃ , NHCSCF ₃ , NHCSR, NHSO ₂ CH ₃ , NHSO ₂ R, OR, COR, OCOR, OSO ₂ R, SO ₂ R, SR, or Q plus a fused ring system in which the benzene ring to which it is attached forms a structure of A, B or C :

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CF ₃ , aryl, phenyl, halogen, alkenyl or OH.

In a specific embodiment, the SARM compound is a compound of formula II wherein X is O. In another SARM compound is a compound of the formula II of the embodiments, wherein Y is CF _3. In another SARM compound is a compound of the formula II of the embodiments, wherein Z is NO _2. In another specific embodiment, the SARM compound is a compound of formula II wherein Z is CN. In another specific embodiment, the SARM compound is a compound of formula II wherein Q is halogen, ie, F, Cl, Br or I. In another SARM compound is a compound of the formula II of the embodiments, wherein Q is NHCOCH _3.

In another SARM compound is a compound of the formula II of the embodiments, wherein X is O, Z is NO _2, Y is CF ₃ and Q is halogen. In another SARM compound is a compound of the formula II of the embodiments, wherein X is O, Z is NO _2, Y is CF ₃ and Q is NHCOCH _3. In another SARM compound is a compound of the formula II of the embodiments, wherein X is O, Z is CN, Y is CF ₃ and Q is halogen. In another SARM compound is a compound of the formula II of the embodiments, wherein X is O, Z is CN, Y is CF ₃ and Q is NHCOCH _2.

In another specific embodiment, it can effectively (1) treat muscle wasting, (2) prevent muscle wasting, and (3) treat, prevent, suppress, inhibit or reduce muscle loss caused by muscle wasting, (4) Treating, preventing, inhibiting, reducing or suppressing muscle loss due to muscle wasting, and/or (5) treating, preventing, inhibiting, reducing or suppressing SARM compound system due to muscle protein dissimilation caused by muscle wasting Compound of formula III:

Wherein X is a bond, O, CH ₂ , NH, Se, PR, NO or NR; G is O or S; R ₁ is CH ₃ , CH ₂ F, CHF ₂ , CF ₃ , CH ₂ CH ₃ or CF ₂ CF ₃ ; T is OH, OR, -NHCOCH ₃ or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CF ₃ , aryl A group, a phenyl group, a halogen, an alkenyl group or an OH; A is a ring selected from the group consisting of:

B is a ring selected from the following:

Wherein A and B cannot be benzene rings at the same time; Z is NO ₂ , CN, COOH, COR, NHCOR or CONHR; Y is CF ₃ , F, I, Br, Cl, CN, CR ₃ or SnR ₃ ; Q ₁ and Q ₂ is independently hydrogen, alkyl, halogen, CF ₃ , CN, CR ₃ , SnR ₃ , NR ₂ , NHCOCH ₃ , NHCOCF ₃ , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH ₃ , NHCSCF ₃ , NHCSR, NHSO ₂ CH ₃ , NHSO ₂ R, OR, COR, OCOR, OSO ₂ R, SO ₂ R, SR,

Q ₃ and Q ₄ are individually independent hydrogen, alkyl, halogen, CF ₃ , CN, CR ₃ , SnR ₃ , NR ₂ , NHCOCH ₃ , NHCOCF ₃ , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH ₃ , NHCSCF ₃ , NHCSR, NHSO ₂ CH ₃ , NHSO ₂ R, OR, COR, OCOR, OSO ₂ R, SO ₂ R or SR; W ₁ is O, NH, NR, NO or S, and W ₂ is N or NO.

In another specific embodiment, it can effectively (1) treat muscle wasting, (2) prevent muscle wasting, and (3) treat, prevent, suppress, inhibit or reduce muscle loss caused by muscle wasting, (4) Treating, preventing, inhibiting, reducing or suppressing muscle loss due to muscle wasting, and/or (5) treating, preventing, inhibiting, reducing or suppressing SARM compound system due to muscle protein dissimilation caused by muscle wasting Compound of formula IV:

Wherein X is a bond, O, CH ₂ , NH, Se, PR, NO or NR; G is O or S; T is OH, OR, -NHCOCH ₃ or NHCOR; R is an alkyl group, a haloalkyl group, a dihalogen Alkyl, trihaloalkyl, CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CF ₃ , aryl, phenyl, halogen, alkenyl or OH; R ₁ is CH ₃ , CH ₂ F, CHF ₂ , CF ₃ , CH ₂ CH ₃ or CF ₂ CF ₃ ; R ₂ is F, Cl, Br, I, CH ₃ , CF ₃ , OH, CN, NO ₂ , NHCOCH ₃ , NHCOCF ₃ , NHCOR, alkyl, aralkyl , OR, NH ₂ , NHR, NR ₂ , SR; R ₃ is F, Cl, Br, I, CN, NO ₂ , COR, COOH, CONHR, CF ₃ , SnR ₃ , or R ₃ plus the The benzene ring forms a fused ring system of the following formula:

Z is NO ₂ , CN, COR, COOH or CONHR; Y is CF ₃ , F, Br, Cl, I, CN or SnR ₃ ; Q is hydrogen, alkyl, halogen, CF ₃ , CN, CR ₃ , SnR ₃ , NR ₂ , NHCOCH ₃ , NHCOCF ₃ , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH ₃ , NHCSCF ₃ , NHCSR, NHSO ₂ CH ₃ , NHSO ₂ R, OH, OR, COR, OCOR, OSO ₂ R, SO ₂ R, SR, or Q plus a fused ring system in which the benzene ring to which it is attached forms the structure of A, B or C:

n is an integer from 1 to 4, and m is an integer from 1 to 3.

In another specific embodiment, it can effectively (1) treat muscle wasting, (2) prevent muscle wasting, and (3) treat, prevent, suppress, inhibit or reduce muscle loss caused by muscle wasting, (4) Treating, preventing, inhibiting, reducing or suppressing muscle loss due to muscle wasting, and/or (5) treating, preventing, inhibiting, reducing or suppressing SARM compound system due to muscle protein dissimilation caused by muscle wasting Compound of the formula:

In a specific embodiment, the administering comprises administering a pharmaceutical composition comprising a SARM and a pharmaceutically acceptable carrier.

In a specific embodiment, the muscle wasting is caused by pathology, illness, disease, or condition. In another specific embodiment, the pathology, illness, disease, or condition is chronic. In another specific embodiment, the pathology, illness, disease, or condition is hereditary. In another specific embodiment, the pathology, illness, disease, or condition is neurogenic. In another embodiment, the pathology, illness, disease, or condition is infectious.

In another embodiment, the pathology, illness, disease, or condition is muscular dystrophy, muscular dystrophy, X-related spinal-bulbar muscular atrophy (SBMA), cachexia, malnutrition, leprosy, diabetes Kidney disease, chronic obstructive pulmonary disease (COPD), cancer, end stage renal failure, poor muscle disease, emphysema, rickets, HIV infection, AIDS and cardiomyopathy.

In another specific embodiment, the muscle wasting is associated with age-related muscle wasting, muscle depletion associated with disuse degradation, or chronic lower back pain, burns, central nervous system (CNS) injury or damage, Muscle wear and tear caused by peripheral nerve injury or damage, spinal injury or damage, chemical injury or damage or alcoholism. In another specific embodiment, the muscle wasting disorder is chronic muscle wasting.

The present invention provides a safe and effective method for treating, preventing, suppressing, inhibiting or reducing muscle loss due to muscle wasting, and is particularly useful for treating a patient's muscle wasting, such as chronic muscle wasting.

The present invention provides: (1) a method for treating a patient's muscle wasting, (2) a method for preventing a patient's muscle wasting, and (3) a method for treating, preventing, suppressing, suppressing or reducing muscle loss in a patient suffering from muscle wasting. (4) A method for treating, preventing, inhibiting, reducing, or suppressing muscle wasting in a patient suffering from muscle wasting, and/or (5) a method for treating, preventing, inhibiting, reducing, or suppressing muscle protein dissimilation in a patient suffering from muscle wasting Method for administering a patient-selective androgen receptor modulator (SARM) and/or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxidation Or any combination thereof.

Accordingly, in one embodiment, the invention provides a method of treating a patient's muscle wasting comprising administering to a patient a selective androgen receptor modulator (SARM) compound and/or an analogue, derivative, or isomer thereof , metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide or any combination thereof.

In another embodiment, the invention provides a method of preventing muscle wasting in a patient comprising administering to a patient a selective androgen receptor modulator (SARM) compound and/or analogues, derivatives, isomers thereof, Metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof.

In another embodiment, the invention provides a method of treating, preventing, suppressing, inhibiting, or reducing muscle loss in a patient suffering from muscle wasting, comprising administering to a patient a selective androgen receptor modulator (SARM) compound and/or An analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide or any combination thereof.

In another embodiment, the invention provides a method of treating, preventing, inhibiting, reducing, or suppressing muscle wasting in a patient suffering from muscle wasting, comprising administering to a patient a selective androgen receptor modulator (SARM) compound and/or An analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide or any combination thereof.

In another embodiment, the invention provides a method of treating, preventing, inhibiting, reducing, or suppressing muscle protein foreignization in a patient suffering from muscle wasting, comprising administering a selective androgen receptor modulator (SARM) compound to a patient / or an analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide or any combination thereof.

Selective androgen receptor modulator (SARMS)

Selective androgen receptor modulators (SARMs) are a class of androgen receptor-specific agents (ARTA) that show the androgenic activity and assimilation activity of non-steroidal ligands on the androgen receptor. These novel agents have utility in treating different hormone-related diseases in males, such as sexual dysfunction, loss of libido, erectile dysfunction, hypogonadism, poor muscle syndrome, osteodystrophy, osteoporosis, cognitive and mood changes, depression , anemia, hair loss, obesity, benign prostatic hyperplasia and / or prostate cancer. Moreover, SARMs have oral sterolone replacement therapy and can be used to scan prostate cancer. In addition, SARMs have utility in treating different hormone-related diseases in females, including, for example, sexual dysfunction, loss of libido, hypogonadism, poor muscle disease, osteodystrophy, osteoporosis, cognitive and mood changes, depression, anemia, Hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer.

In a specific embodiment, it can effectively (1) treat muscle wasting, (2) prevent muscle wasting, (3) treat, prevent, suppress, inhibit or reduce muscle loss caused by muscle wasting, (4) Treat, prevent, inhibit, reduce or suppress muscle loss due to muscle wasting, and/or (5) treat, prevent, inhibit, reduce or suppress SARM compound system due to muscle protein dissimilation caused by muscle wasting Compound of I:

Wherein G is O or S, X is a bond, O, CH ₂ , NH, Se, PR, NO or NR; T is OH, OR, -NHCOCH ₃ or NHCOR; Z is NO ₂ , CN, COOH, COR, NHCOR or CONHR; Y is CF ₃ , F, I, Br, Cl, CN, CR ₃ or SnR ₃ ; Q is alkyl, halogen, CF ₃ , CN, CR ₃ , SnR ₃ , NR ₂ , NHCOCH ₃ , NHCOCF ₃ , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH ₃ , NHCSCF ₃ , NHCSR, NHSO ₂ CH ₃ , NHSO ₂ R, OR, COR, OCOR, OSO ₂ R, SO ₂ R, SR, or Q plus A fused ring system in which the attached benzene ring forms a structure of A, B or C:

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CF ₃ , aryl, phenyl, halogen, alkenyl or OH, and R ₁ Is CH ₃ , CH ₂ F, CHF ₂ , CF ₃ , CH ₂ CH ₃ or CF ₂ CF ₃ .

In a specific embodiment, the SARM is an analog of a compound of formula I. In another specific embodiment, the SARM is a derivative of a compound of formula I. In another specific embodiment, the SARM is an isomer of a compound of formula I. In another specific embodiment, the SARM is a metabolite of a compound of formula I. In another specific embodiment, the SARM is a pharmaceutically acceptable salt of a compound of formula I. In another specific embodiment, the SARM is a pharmaceutical product of a compound of formula I. In another specific embodiment, the SARM is a hydrate of a compound of formula I. In another embodiment, the SARM is an N-oxide of a compound of formula I. In another specific embodiment, the SARM is an analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide combination of any of the compounds of Formula I.

In a specific embodiment, the SARM compound is a compound of formula I, wherein X is O. In a specific embodiment, the SARM compound is a compound of formula I, wherein G is O. In another SARM compound is a compound of the formula I of particular embodiments, wherein Z is NO _2. In another specific embodiment, the SARM compound is a compound of formula I, wherein Z is CN. In another SARM compound is a compound of the formula I of particular embodiments, wherein Y is CF _3. In another SARM compound is a compound of the formula I of particular embodiments, wherein Q is NHCOCH _3. In another specific embodiment, the SARM compound is a compound of formula I, wherein Q is F. In another specific embodiment, the SARM compound is a compound of formula I, wherein T is OH. In another SARM compound is a compound of the formula I of particular embodiments, in which R ₁ is CH _3.

In another specific embodiment, it can effectively (1) treat muscle wasting, (2) prevent muscle wasting, and (3) treat, prevent, suppress, inhibit or reduce muscle loss caused by muscle wasting, (4) Treating, preventing, inhibiting, reducing or suppressing muscle loss due to muscle wasting, and/or (5) treating, preventing, inhibiting, reducing or suppressing SARM compound system due to muscle protein dissimilation caused by muscle wasting Compound of formula II:

Wherein X is a bond, O, CH ₂ , NH, Se, PR, NO or NR; Z is NO ₂ , CN, COOH, COR, NHCOR or CONHR; Y is CF ₃ , F, I, Br, Cl, CN , CR ₃ or SnR _3; Q is alkyl, _{halo, CF 3, CN, CR 3} , SnR 3, NR 2, NHCOCH 3, NHCOCF 3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3, NHCSCF 3, NHCSR, NHSO ₂ CH ₃ , NHSO ₂ R, OR, COR, OCOR, OSO ₂ R, SO ₂ R, SR, or Q plus a fused ring system in which the benzene ring to which it is attached forms a structure of A, B or C :

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CF ₃ , aryl, phenyl, halogen, alkenyl or OH.

In a specific embodiment, the SARM is an analog of a compound of formula II. In another specific embodiment, the SARM is a derivative of a compound of formula II. In another specific embodiment, the SARM is an isomer of a compound of formula II. In another specific embodiment, the SARM is a metabolite of a compound of formula II. In another specific embodiment, the SARM is a pharmaceutically acceptable salt of a compound of formula II. In another specific embodiment, the SARM is a pharmaceutical product of a compound of formula II. In another specific embodiment, the SARM is a hydrate of a compound of formula II. In another embodiment, the SARM is an N-oxide of a compound of formula II. In another specific embodiment, the SARM is an analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide combination of a compound of formula II.

In a specific embodiment, the SARM compound is a compound of formula II wherein X is O. In another SARM compound is a compound of the formula II of the embodiments, wherein Z is NO _2. In another specific embodiment, the SARM compound is a compound of formula II wherein Z is CN. In another SARM compound is a compound of the formula II of the embodiments, wherein Y is CF _3. In another SARM compound is a compound of the formula II of the embodiments, wherein Q is NHCOCH _3. In another specific embodiment, the SARM compound is a compound of formula II wherein Q is F. In another specific embodiment, the SARM compound is a compound of formula II wherein Q is halogen, ie, F, Cl, Br or I.

In another SARM compound is a compound of the formula II of the embodiments, wherein X is O, Z is NO _2, Y is CF ₃ and Q is halogen. In another embodiment, the SARM compound is a compound of formula II wherein X is O, Z is NO ₂ , Y is CF ₃ and Q is NHCOCH ₂ . In another SARM compound is a compound of the formula II of the embodiments, wherein X is O, Z is CN, Y is CF ₃ and Q is halogen. In another SARM compound is a compound of the formula II of the embodiments, wherein X is O, Z is CN, Y is CF ₃ and Q is NHCOCH _3.

In another specific embodiment, it can effectively (1) treat muscle wasting, (2) prevent muscle wasting, and (3) treat, prevent, suppress, inhibit or reduce muscle loss caused by muscle wasting, (4) Treating, preventing, inhibiting, reducing or suppressing muscle loss due to muscle wasting, and/or (5) treating, preventing, inhibiting, reducing or suppressing SARM compound system due to muscle protein dissimilation caused by muscle wasting Compound of formula III:

Wherein X is a bond, O, CH ₂ , NH, Se, PR, NO or NR; G is O or S; R ₁ is CH ₃ , CH ₂ F, CHF ₂ , CF ₃ , CH ₂ CH ₃ or CF ₂ CF ₃ ; T is OH, OR, -NHCOCH ₃ or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CF ₃ , aryl A group, a phenyl group, a halogen, an alkenyl group or an OH; A is a ring selected from the group consisting of:

B is a ring selected from the following:

Wherein A and B cannot be benzene rings at the same time, Z is NO ₂ , CN, COOH, COR, NHCOR or CONHR, Y is CF ₃ , F, I, Br, Cl, CN, CR ₃ or SnR ₃ , Q ₁ and Q ₂ is independently hydrogen, alkyl, halogen, CF ₃ , CN, CR ₃ , SnR ₃ , NR ₂ , NHCOCH ₃ , NHCOCF ₃ , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH ₃ , NHCSCF ₃ , NHCSR, NHSO ₂ CH ₃ , NHSO ₂ R, OR, COR, OCOR, OSO ₂ R, SO ₂ R, SR,

Q ₃ and Q ₄ are individually independent hydrogen, alkyl, halogen, CF ₃ , CN, CR ₃ , SnR ₃ , NR ₂ , NHCOCH ₃ , NHCOCF ₃ , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH ₃ , NHCSCF ₃ , NHCSR, NHSO ₂ CH ₃ , NHSO ₂ R, OR, COR, OCOR, OSO ₂ R, SO ₂ R or SR; W ₁ is O, NH, NR, NO or S, and W ₂ is N or NO.

In a specific embodiment, the SARM is an analog of a compound of formula III. In another specific embodiment, the SARM is a derivative of a compound of formula III. In another specific embodiment, the SARM is an isomer of a compound of formula III. In another specific embodiment, the SARM is a metabolite of a compound of formula III. In another specific embodiment, the SARM is a pharmaceutically acceptable salt of a compound of formula III. In another specific embodiment, the SARM is a pharmaceutical product of a compound of formula III. In another embodiment, the SARM is a hydrate of a compound of formula III. In another embodiment, the SARM is an N-oxide of a compound of formula III. In another specific embodiment, the SARM is an analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide combination of any of the compounds of Formula III.

In a specific embodiment, the SARM compound is a compound of formula III wherein X is O. In another specific embodiment, the SARM compound is a compound of formula III wherein G is O. In another specific embodiment, the SARM compound is a compound of formula III wherein T is OH. In another SARM compound is the compound of the formula III embodiments, in which R ₁ is CH _3. In another SARM compound is the compound of the formula III embodiments, wherein Z is NO _2. In another specific embodiment, the SARM compound is a compound of formula III wherein Z is CN. In another SARM compound is the compound of the formula III embodiments, wherein Y is CF _3. In another SARM compound is the compound of the formula III embodiments, wherein Q ₁ is NHCOCH _3. In another SARM compound is the compound of the formula III embodiments, wherein Q ₁ is F.

The substituents Z and Y may be located at any position of the ring carrying these substituents (hereinafter referred to as "A ring"). In a particular embodiment, the substituent Z is located in the para position of the A ring. In another specific embodiment, the substituent Y is located between the A rings. In another embodiment, the substituent Z is in the para position of the A ring and the substituent Y is in the position between the A rings.

The substituents Q ₁ and Q ₂ may be located at any position of a ring carrying these substituents (hereinafter referred to as "B ring"). In a particular embodiment, the substituent Q ₁ is located in the para position of the B ring. In another specific embodiment, the substituent Q ₂ is H. In another specific embodiment, the substituent Q ₁ is in the para position of the B ring and the substituent Q ₂ is H. In another specific embodiment, the substituent Q ₁ is NHCOCH ₃ and is located in the para position of the B ring, and the substituent Q ₂ is H.

In another specific embodiment, it can effectively (1) treat muscle wasting, (2) prevent muscle wasting, and (3) treat, prevent, suppress, inhibit or reduce muscle loss caused by muscle wasting, (4) Treating, preventing, inhibiting, reducing or suppressing muscle loss due to muscle wasting, and/or (5) treating, preventing, inhibiting, reducing or suppressing SARM compound system due to muscle protein dissimilation caused by muscle wasting Compound of formula IV:

Wherein X is a bond, O, CH ₂ , NH, Se, PR, NO or NR; G is O or S; T is OH, OR, -NHCOCH ₃ or NHCOR; R is an alkyl group, a haloalkyl group, a dihalogen Alkyl, trihaloalkyl, CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CF ₃ , aryl, phenyl, halogen, alkenyl or OH; R ₁ is CH ₃ , CH ₂ F, CHF ₂ , CF ₃ , CH ₂ CH ₃ or CF ₂ CF ₃ ; R ₂ is F, Cl, Br, I, CH ₃ , CF ₃ , OH, CN, NO ₂ , NHCOCH ₃ , NHCOCF ₃ , NHCOR, alkyl, aralkyl , OR, NH ₂ , NHR, NR ₂ , SR; R ₃ is F, Cl, Br, I, CN, NO ₂ , COR, COOH, CONHR, CF ₃ , SnR ₃ , or R ₃ plus the The benzene ring forms a fused ring system of the following formula:

Z is NO ₂ , CN, COR, COOH or CONHR; Y is CF ₃ , F, Br, Cl, I, CN or SnR ₃ ; Q is hydrogen, alkyl, halogen, CF ₃ , CN, CR ₃ , SnR ₃ , NR ₂ , NHCOCH ₃ , NHCOCF ₃ , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH ₃ , NHCSCF ₃ , NHCSR, NHSO ₂ CH ₃ , NHSO ₂ R, OH, OR, COR, OCOR, OSO ₂ R, SO ₂ R, SR, or Q plus a fused ring system in which the benzene ring to which it is attached forms the structure of A, B or C:

n is an integer from 1 to 4, and m is an integer from 1 to 3.

In a specific embodiment, the SARM is an analog of a compound of formula IV. In another specific embodiment, the SARM is a derivative of a compound of formula IV. In another specific embodiment, the SARM is an isomer of a compound of formula IV. In another specific embodiment, the SARM is a metabolite of a compound of formula IV. In another specific embodiment, the SARM is a pharmaceutically acceptable salt of a compound of formula IV. In another specific embodiment, the SARM is a pharmaceutical product of a compound of formula IV. In another specific embodiment, the SARM is a hydrate of a compound of formula IV. In another embodiment, the SARM is an N-oxide of a compound of formula IV. In another specific embodiment, the SARM is an analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide combination of a compound of formula IV.

In a specific embodiment, the SARM compound is a compound of formula IV wherein X is O. In another specific embodiment, the SARM compound is a compound of Formula IV wherein G is O. In another SARM compound is a compound of the formula IV of the embodiments, wherein Z is NO _2. In another specific embodiment, the SARM compound is a compound of Formula IV wherein Z is CN. In another SARM compound is a compound of the formula IV of the embodiments, wherein Y is CF _3. In another SARM compound is a compound of the formula IV of the embodiments, wherein Q is NHCOCH _3. In another specific embodiment, the SARM compound is a compound of formula IV wherein Q is F. In another specific embodiment, the SARM compound is a compound of formula IV wherein T is OH. In another SARM compound is a compound of the formula IV of the embodiments, in which R ₁ is CH _3. In another specific embodiment, the SARM compound is a compound of Formula IV wherein Q is F and R ₂ is CH ₃ . In another specific embodiment, the SARM compound is a compound of Formula IV wherein Q is F and R ₂ is Cl.

The substituents Z, Y and R ₃ may be located at any position of the ring carrying these substituents (hereinafter referred to as "A ring"). In a particular embodiment, the substituent Z is located in the para position of the A ring. In another specific embodiment, the substituent Y is located between the A rings. In another embodiment, the substituent Z is in the para position of the A ring and the substituent Y is in the position between the A rings.

The substituents Q and R ₂ may be located at any position of the ring carrying these substituents (hereinafter referred to as "B ring"). In a specific embodiment, the substituent Q is located in the para position of the B ring. In another specific embodiment, the substituent Q ₁ is NHCOCH ₃ and is located in the para position of the B ring.

As contemplated herein, when both m and n are integers greater than 1, the substituents R ₂ and R ₃ are not limited to a particular substituent and are taken as any combination of the above substituents.

In another specific embodiment, it can effectively (1) treat muscle wasting, (2) prevent muscle wasting, and (3) treat, prevent, suppress, inhibit or reduce muscle loss caused by muscle wasting, (4) Treating, preventing, inhibiting, reducing or suppressing muscle loss due to muscle wasting, and/or (5) treating, preventing, inhibiting, reducing or suppressing SARM compound system due to muscle protein dissimilation caused by muscle wasting Compound of formula V:

In a specific embodiment, the SARM is an analog of a compound of formula V. In another embodiment, the SARM is a derivative of a compound of formula V. In another embodiment, the SARM is an isomer of a compound of formula V. In another specific embodiment, the SARM is a metabolite of a compound of formula V. In another specific embodiment, the SARM is a pharmaceutically acceptable salt of a compound of formula V. In another embodiment, the SARM is a pharmaceutical product of a compound of formula V. In another embodiment, the SARM is a hydrate of a compound of formula V. In another embodiment, the SARM is an N-oxide of a compound of formula V. In another embodiment, the SARM is an analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide combination of any of the compounds of formula V.

In another specific embodiment, it can effectively (1) treat muscle wasting, (2) prevent muscle wasting, and (3) treat, prevent, suppress, inhibit or reduce muscle loss caused by muscle wasting, (4) Treating, preventing, inhibiting, reducing or suppressing muscle loss due to muscle wasting, and/or (5) treating, preventing, inhibiting, reducing or suppressing SARM compounds caused by muscle protein dissimilation caused by muscle wasting, Compounds under the formula:

And/or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides, or any combination thereof.

The R substituent of the SARM compound of the present invention is defined herein as alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CF ₃ , aryl, benzene. Base, halogen, alkenyl or OH.

"Alkyl" means a saturated aliphatic hydrocarbon group including straight chain, branched chain and cycloalkyl groups. In a particular embodiment, the alkyl group has from 1 to 12 carbon atoms. In another specific embodiment, the alkyl group has from 1 to 7 carbon atoms. In another specific embodiment, the alkyl group has from 1 to 6 carbon atoms. In another specific embodiment, the alkyl group has from 1 to 4 carbon atoms. The alkyl group is unsubstituted or substituted, and the substituent is selected from the group consisting of halogen, hydroxy, alkoxycarbonyl, decylamino, alkyl guanylamino, dialkyl decylamino, nitro, amine. Alkyl, alkylamino, dialkylamino, carboxy, thio and sulfanyl.

"Alkenyl" means an unsaturated hydrocarbon group including straight chain, branched chain and cyclic groups having one or more double bonds. The alkenyl group has one, two or three double bonds and the like. Examples of alkenyl groups are ethenyl, propenyl, butenyl, cyclohexenyl and the like. The alkenyl group is unsubstituted or substituted, and the substituent is selected from the group consisting of halogen, hydroxy, alkoxycarbonyl, decylamino, alkyl decylamino, dialkyl decylamino, nitro, amine An alkylamino group, a dialkylamino group, a carboxyl group, a thio group and a sulfanyl group.

"Haloalkyl" means a substituent of the above alkyl group substituted with one or more halogen atoms, such as F, Cl, Br or I.

"Aryl" means an aryl group having at least one carbonyl ring aryl or heterocyclic aryl group which is unsubstituted or selected from one or more, halogen, haloalkyl, hydroxy, alkoxycarbonyl, hydrazine Substituted by an amine group, an alkylguanamine group, a dialkylguanidinyl group, a nitro group, an amine group, an alkylamino group, a dialkylamino group, a carboxyl group or a thio group or a thioalkyl group. Non-limiting examples of aromatic rings include phenyl, naphthyl, piperidyl, pyrrolinyl, pyridyl Base, pyrimidinyl, pyrazolyl, pyridyl, furyl, thiophenyl, thiazolyl, imidazolyl, iso Azolyl and analogs.

"Hydroxy" means an OH group. It is of course understood by those skilled in the art that when T in the compounds of the invention is OR, R is non-OH. Halogen means F, Cl, Br or I. "Aralkyl" means an alkyl group bonded to an aryl group, wherein the alkyl group and the aryl group are as defined above. One of the examples of the aralkyl group is a benzyl group.

As contemplated herein, the invention relates to the treatment of SARM compounds and/or their analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides, or combinations thereof. / Use to prevent muscle wasting. Thus, in one embodiment, the method of the invention comprises administering an analog of the SARM. In another specific embodiment, the method of the invention comprises administering a derivative of the SARM. In another embodiment, the method of the invention comprises administering an isomer of the SARM. In another specific embodiment, the method of the invention comprises administering a metabolite of the SARM. In another embodiment, the method of the invention comprises administering a pharmaceutically acceptable salt of the SARM. In another embodiment, the method of the invention comprises administering a pharmaceutical product of the SARM. In another embodiment, the method of the invention comprises administering a hydrate of the SARM. In another embodiment, the method of the invention comprises administering an N-oxide of the SARM. In another specific embodiment, the method of the invention comprises administering any of the analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides of the SARM compound. combination.

As used herein, "isomers" include, but are not limited to, optical isomers and analogs, structural isomers and analogs, conformational isomers and analogs, and the like.

In a specific embodiment, the invention encompasses the use of different optical isomers of SARM compounds. Those skilled in the art will appreciate that the SARMs of the present invention contain at least one palm-shaped center. Accordingly, the SARMs used in the method of the invention are present and can be isolated for optically active or racemic forms. Some compounds also have homomorphic polymorphism. Of course, the invention encompasses any racemic, optically active, homogeneous polymorphic, or stereoisomeric forms, or mixtures thereof, for use in the treatment of the androgen-related disorders described herein. In a specific embodiment, the SARMs are pure (R)-isomers. In another specific embodiment, the SARMs are pure (S)-isomers. In another specific embodiment, the SARMs are a mixture of (R)- and (S)-isomers. In another embodiment, the SARMs comprise a racemic mixture of equal amounts of (R)- and (S)-isomers. Methods for preparing optically active forms have been well documented in the art (for example, derotation of racemic mixtures by recrystallization techniques, synthesis of optically active starting materials, palm-shaped synthesis or chromatographic analysis using palm-type stationary phases) ).

The present invention includes "pharmaceutically acceptable salts" of compounds substituted with an amine group of an organic and inorganic acid such as citric acid and hydrochloric acid. The invention also includes the amine-substituted N-oxides of the compounds described herein. Pharmaceutically acceptable salts are also prepared from phenolic compounds using inorganic bases such as sodium hydroxide. Further, esters of phenolic compounds are obtained from aliphatic and aromatic carboxylic acids such as acetic acid and benzoic acid esters.

The invention further includes derivatives of SARMs. The term "derivative" includes, but is not limited to, ether derivatives, acid derivatives, decylamine derivatives, ester derivatives, and the like. Furthermore, the invention further includes hydrates of SARMs. The term "hydrate" includes, but is not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, and the like.

The invention further encompasses metabolites of SARM compounds. The term "metabolite" means a substance produced by another substance via metabolism or metabolic processes.

The invention further encompasses pharmaceutical products of SARM compounds. The term "pharmaceutical product" means a composition suitable for medical use as described herein.

Biological activity of selective androgen regulator compounds

As contemplated herein, the SARM compounds of the invention have utility in the treatment, prevention, suppression, inhibition or reduction of muscle wasting as described herein. The complete androgen receptor (AR) signaling pathway is important for proper development of skeletal muscle. Moreover, the complete AR signaling pathway increases lean meat mass, muscle strength and muscle protein synthesis.

The muscle system is mainly used as the organization of the power source function. Our body has three muscles: (a) skeletal muscle - the muscle that is responsible for movement to the extreme and the outside of the body, (b) the muscle-heart muscle (c) the smooth muscle - the muscle located in the arterial and intestinal wall.

A depleted condition or disorder is defined herein as a condition or disorder in which at least some of the abnormal body, organ or tissue quality continues to be lost. The occurrence of depletion may be the result of pathology, such as cancer; or may be due to physiological or metabolic states, such as disuse that may be caused by prolonged bed rest or limb immobilization such as when plastering. Depletion of the condition may also be related to age. The loss of body mass caused by depletion of the condition may be characterized by a reduction in overall weight or a reduction in the mass of the organ that loses bone or muscle mass, such as a decrease in tissue protein.

The term "muscle wear" or "muscle wear" used interchangeably herein means continuous loss of muscle mass and/or persistent weakness and deterioration of muscles, including skeletal or voluntary muscles that control exercise. Controls the heart's myocardium and smooth muscle. In a specific embodiment, the muscle depleting condition or condition is a chronic muscle depletion of the condition or disorder. "Chronic muscle depletion" is defined herein as a chronic (ie, sustained for a long period of time) sustained loss of muscle mass and/or chronic muscle weakness and degeneration.

The loss of muscle mass that occurs during muscle depletion can be characterized by muscle protein destruction or degradation caused by muscle protein dissimilation. Protein catabolism can occur due to abnormally high rates of protein degradation, abnormally low rate protein synthesis, or a combination of both. Protein catabolism or consumption, whether it is abnormally high rate of protein degradation or abnormally low rate of protein synthesis, can result in reduced muscle mass and muscle loss. The term "alienation" has a well-known meaning in this art, and it refers specifically to the energy burning pattern in the metabolic process.

Muscle depletion can also result from pathology, disease, condition or condition. In a specific embodiment, the pathology, illness, disease, or condition is chronic. In another specific embodiment, the pathology, illness, disease, or condition is hereditary. In another specific embodiment, the pathology, illness, disease, or condition is neurogenic. In another embodiment, the pathology, illness, disease, or condition is infectious. As described herein, the pathology, disease, condition or condition to which the compound of the invention and the composition are to be administered are those which directly or indirectly produce muscle mass depletion (i.e., loss), i.e., muscle wasting.

These include, but are not limited to, muscular dystrophy, muscular dystrophy, cachexia, malnutrition, leprosy, diabetes, kidney disease, chronic obstructive pulmonary disease (COPD), cancer, end stage renal failure, poor muscle disease, emphysema , rickets, HIV infection, AIDS and cardiomyopathy.

In another specific embodiment, the muscle was impaired by infectious diseases such as enterovirus, Epstein-Barr virus, banded rash, HIV, trypanosomiasis, cold, keshavirus, infectious mononuclear disease, ricketts Caused by secondary infection, trichinosis or schistosomiasis.

Muscular dystrophy is a hereditary disease characterized by persistent weakness and degradation of skeletal or voluntary muscles that control exercise. Myocardium or certain involuntary muscles are also affected by certain types of muscular dystrophy. The main types of muscular dystrophy are Duchenne muscular dystrophy, myotonic dystrophy, Becker muscular dystrophy, ring muscle dystrophy, diaphragmatic dystrophy, congenital muscular dystrophy, Osopharyngeal dystrophy, peripheral muscle dystrophy and Emery-Dreifuss muscle dystrophy.

Muscular dystrophy also affects people of all ages. Although some patterns are particularly noticeable in infants or children, others may occur in middle age or later. Duchenne muscular dystrophy is the most common affecting muscular dystrophy in children. Myotonia dystrophy is the most common cause of these diseases in adults.

Muscular atrophy is characterized by the disappearance or reduction of muscle atrophy and the reduction in muscle mass. For example, muscular dystrophy in post-epidemic polio is a part of the muscle loss of the epidemic polio inflammatory syndrome (PPS). The atrophy includes weakness, muscle fatigue and pain.

Another type of muscular dystrophy is X-associated spinal-bulbar muscular atrophy (SBMA-also known as gandidi). This disease is caused by a defect in the androgen receptor gene on the X chromosome, affecting only men, and its occurrence is after adulthood. Because the cause of primary disease is the male hormone receptor mutation, androgen replacement is not the current treatment strategy. In some investigations, we administered exogenous steroid ketone to increase the amount of androgen, to see if it can overcome androgen insensitivity and may provide assimilation. However, the use of super-physiological amounts of testosterone as a supplement has its limitations and other potentially serious complications.

The cachexia is debilitated and lost due to the side effects of the disease or illness. Myocardial cachexia, which is the muscle protein loss of both myocardium and skeletal muscle, is characteristic of obstructive heart failure. The cancer cachexia has a syndrome that occurs in patients with solid tumors or tissue malignancy, and its clear evidence of weight loss in the mass reduction of adipose tissue and lean meat mass. Acquired immunodeficiency syndrome (AIDS) cachexia is associated with human immunodeficiency virus (HIV)-associated muscle disease and/or muscle weakness/depletion, a fairly common clinical feature of AIDS. People with HIV-related muscle disease or muscle weakness or depletion typically have significant weight loss, general or proximal muscle weakness, weakness and muscle wasting.

The poor muscle system affects the debilitating disease of the elderly and chronic patients, characterized by loss of muscle mass and function. [Nair K. S. Mayo Clin Proc 2000 Jan; 75 Suppl: S14-8]. We confirm that assimilated steroids prevent and/or reverse the loss of lean body mass associated with age, disease, and severe trauma (skeletal muscle mass loss) [Sheffield-Moore, Ann. Med. 32:181-186, 2000; Bhasin, S. Mayo Clin Proc 2000 Jan; 75 Suppl: S70-5]. Moreover, the increase in lean body mass is associated with a reduction in the morbidity and mortality of certain muscle-depleting diseases.

In addition, other environments are associated with the condition and can cause muscle wasting. For example, studies have shown that under severe conditions, there is a loss of muscles in the lower back.

Muscle depletion is associated with old age. The general weakness of the elderly is due to muscle loss. As the body ages, more and more skeletal muscles are replaced by fibrous tissue. The result is a significant reduction in muscle strength, performance and endurance.

Long-term hospitalization for illness or injury or depletion of disability due to, for example, limb movement can cause muscle wasting. Studies have shown that patients with injuries, chronic diseases, burns, trauma, or cancer can have long-term sustained unilateral muscle loss if they are hospitalized for a long period of time, and then the body mass will be reduced.

Injury or damage to the central nervous system (CNS) is also associated with muscle wasting disease. CNS injuries or damage may be caused by diseases such as illness, trauma or chemicals. Examples are injuries or damage to the central nervous system, injury or damage to the peripheral nerves, and injury or damage to the spine.

Finally, alcoholism has been shown to be associated with muscle wasting.

As encompassed herein, the invention provides a class of compounds that are selective androgen receptor modulators (SARMs). We classify these compounds for use in the treatment and prevention of muscle wasting as androgen receptor agonists (AR agonists), partial agonists or androgen receptor antagonists (AR antagonists).

Receptor agonists bind to receptors and activate their substances. Partial agonists of the receptor bind to the receptor and partially activate their material. Receptor antagonists bind to receptors and inhibit their substances. As shown herein, the SARM compounds of the invention have a tissue selective effect, wherein depending on the tissue, an agent may be an agonist, a partial agonist and/or an antagonist. For example, SARM compounds may stimulate muscle tissue while inhibiting prostate tissue. In a specific embodiment, the SARMs-based AR agonist for use in the treatment and prevention of muscle wasting; therefore, has the use of binding and activating the AR. In another specific embodiment, the SARMs are AR antagonists; therefore, have the utility of binding and inhibiting the AR. It is well known to those skilled in the art that the compounds of the invention are assayed as AR agonists or antagonists. For example, AR agonist activity can be determined by detecting the ability of a SARM compound to maintain and/or stimulate the growth of AR-containing tissues, such as the prostate and seminal vesicles. AR antagonist activity can be determined by detecting the ability of a SARM compound to inhibit the growth of AR-containing tissue.

In another embodiment, we can classify the SARM compounds of the invention as partial AR agonists/antagonists. The SARMs in certain tissue AR agonists result in increased translation of AR response genes (eg, muscle assimilation effects). In other tissues, these compounds act as competitive inhibitors of AR steroid/DHT to prevent the kinetin effect of native androgen.

The SARM compounds of the invention will form a reversible or irreversible binding to the androgen receptor. In a specific embodiment, the SARM compound forms a reversible binding to the androgen receptor. In another specific embodiment, the SARM compound forms an irreversible binding to the androgen receptor. The compounds of the invention are intended to comprise a functional group (affinity tag) which allows alkylation of the androgen receptor (i.e., formation of a covalent bond). Thus, in this case, the compound will form an irreversible binding to the receptor; accordingly, it cannot be substituted by a steroid such as DHT and the endogenous ligand of the testosterone.

The present invention provides a safe and effective treatment, prevention, suppression, inhibition or reduction of muscle loss and/or muscle protein dissimilation due to muscle depletion; and, in particular, the use of treating a patient's muscle wasting. In a specific embodiment, the patient is a mammal. In another specific embodiment, the patient is a human. In another specific embodiment, the patient is male. In another specific embodiment, the patient is a female.

Pharmaceutical composition

The invention provides a composition and a pharmaceutical composition for treating a patient's muscle wasting, preventing muscle wasting, treating, preventing, suppressing, inhibiting or reducing muscle loss in a patient suffering from muscle wasting, treating, preventing, inhibiting, reducing or suppressing muscle wasting The use of muscle loss and treatment, prevention, inhibition, reduction or suppression of muscle protein foreignization in patients with muscle wasting, which is administered to the patient's selective androgen receptor modulator (SARM) and/or its analogs, , an isomer, a metabolite, a pharmaceutically acceptable salt, a pharmaceutical product, a hydrate, an N-oxide, or any combination thereof, and a pharmaceutically acceptable carrier.

As used herein, "pharmaceutical composition" means a "pharmaceutically effective amount" of an active ingredient, that is, a SARM compound plus a pharmaceutically acceptable carrier or diluent. As used herein, "pharmaceutically effective amount" means providing a particular condition and the therapeutic effect of the method of administration.

The pharmaceutical composition containing the SARM agent can be administered to a patient by methods known to the artist, such as parenteral, paracancerous, transmucosal, transdermal, intramuscular, intravenous, intradermal, Subcutaneous, intraperitoneal, intraventricular, intracranial, intravaginal or intratumoral.

In a particular embodiment, the pharmaceutical composition is administered orally and is therefore formulated for oral administration, i.e., as a solid or liquid formulation. Suitable solid oral formulations include lozenges, capsules, pills, granules, tablets, and the like. Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils, and the like. In a specific embodiment of the invention, the SARM compound is formulated as a capsule. According to this embodiment, the compositions of the present invention comprise, in addition to the SARM active compound and a carrier or diluent, a hard gel capsule.

Moreover, in another embodiment, the pharmaceutical composition is an administration form for intravenous, intraarterial or intramuscular injection of a liquid formulation. Suitable liquid formulations include solutions, suspensions, dispersions, emulsions, oils, and the like. In a particular embodiment, the pharmaceutical composition is administered intravenously and is therefore formulated for intravenous administration. In another specific embodiment, the pharmaceutical composition is administered intra-arterially and is therefore formulated for an arterial administration pattern. In another specific embodiment, the pharmaceutical composition is administered intramuscularly and is therefore formulated for an intramuscular application.

Moreover, in another embodiment, the pharmaceutical composition is topically applied to the body surface and is thus formulated for topical application. Suitable topical formulations include gels, ointments, creams, lotions, drops, and the like. For topical administration, we prepare the SARM agent or a physiologically tolerable derivative thereof such as a salt, an ester, an N-oxide and the like in a physiologically acceptable diluent, with or without a pharmaceutical carrier, as Use as a solution, suspension or emulsion.

Moreover, in another embodiment, the pharmaceutical composition is administered as a suppository, such as a rectal suppository or a urethral suppository. Moreover, in another embodiment, the pharmaceutical composition is administered using a tablet implanted subcutaneously. In another embodiment, the tablet provides controlled release of the SARM agent over a period of time.

In another embodiment, the active compound can be delivered in a capsular cell, particularly a liposome (see Langer, Science 249: 1527-1533 (1990); Treat et al., Liposomes in the Therapy of Infectious Disease and Cancer , Lopez-Berestein and Fidler (editor), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, supra, pages 317-327; generally refer to the same part).

As used herein, "pharmaceutically acceptable carrier or diluent" is well known to those skilled in the art. The carrier or diluent may be a solid carrier or diluent for solid formulation; a liquid carrier or diluent for liquid formulation; or a mixture thereof.

Solid carriers/diluents include, but are not limited to, gums, starches (eg, corn starch pregelatinized starch), sugars (eg, lactose, mannitol, sucrose, glucose), cellulosic materials (microcrystalline cellulose, carboxymethyl cellulose) ), cyclodextrin, acrylate (eg polymethacrylate), calcium carbonate, magnesium oxide, talc or mixtures thereof.

For liquid formulation, the pharmaceutically acceptable carrier can be an aqueous or non-aqueous solution, suspension, emulsion or oil. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline solutions and buffering media. Examples of oils are petroleum, animal, vegetable or synthetic sources such as peanut oil, soybean oil, mineral oil, olive oil, sunflower oil and cod liver oil.

Parenteral vehicles (for subcutaneous, intravenous, intraarterial or intramuscular injection) include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's solution and fixed oil. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers, such as according to Ringer's dextrose solution and the like. Examples thereof are sterile liquids such as water and oil with or without a surfactant and other pharmaceutically acceptable adjuvants. In general, water, saline, aqueous dextrose and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, especially when injectable solutions. Examples of oils are petroleum, animal, vegetable or synthetic sources such as peanut oil, soybean oil, mineral oil, olive oil, sunflower oil and cod liver oil.

Further, the composition may further comprise a binding agent (for example, gum arabic, corn starch, gelatin, carbomer, ethyl cellulose, silicone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pyrrolidone). ), decomposers (such as corn starch, potato starch, alginic acid, ceria, croscarmelose sodium, crospovidone, tannin, sodium starch glycolate), buffers of different pH and ionic strength (eg (Tris-HCl, acetate) , phosphates, additives such as albumin or gelatin to prevent adsorption on the surface, detergents (eg Tween 20, Tween 80, Pluronic F68, cholate), protease inhibitors, surfactants (eg sodium lauronate) ), penetration enhancers, stabilizers (eg glycerol, polyethylene glycerol), antioxidants (eg ascorbic acid, sodium metabisulfite, hydroxymethoxybenzoate), stabilizers (hydroxypropylcellulose, hydroxypropylmethyl) Cellulose), viscosity enhancers (such as carbomer preparations, colloidal cerium oxide, ethyl cellulose, silicone), sweeteners (such as aspartame and citric acid), preservatives (such as Thimerosal, benzyl) alcohol, Benzoate), lubricants (such as stearic acid, magnesium stearate, polyethylene glycol, sodium laurate), flow aids (such as colloidal cerium oxide), plasticizers (such as tannic acid Ethyl ester, triethyl citrate), emulsifier (such as carbomer preparation, hydroxypropyl cellulose, sodium decanoate), polymer coating (such as polyhydroxy hydrocarbon or Pauline), Coating with a film former (such as ethyl cellulose, acrylate, polymethacrylate) and/or an adjuvant.

In a particular embodiment, the pharmaceutical composition provides a controlled release composition, i.e., the SARM compound is a composition that is released over a period of time after administration. Controlled or sustained release compositions include coating in a lipophilic depot (e.g., fatty acids, waxes, oils). In another embodiment, the composition is an immediate release composition, i.e., the SARM compound is a composition that is fully released immediately after administration.

In another embodiment, the pharmaceutical composition is delivered via a controlled release system. For example, the agent can be administered using a venous infiltration, an implantable osmotic pressure pump, a transdermal patch, liposomes, or other modes of administration. A pump is used in a specific embodiment (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88: 507 (1980); Saudek et al. ., N. Engl. J. Med. 321:574 (1989)). In another embodiment, a polymer is used. In another embodiment, a controlled release system is placed adjacent to the treatment target, i.e., the brain, and thus only a partial systemic dose is required (see, for example, Goodson, Medical Application of Controlled Release, supra, Volume 2). , pp. 115-138 (1984)). Other controlled release systems refer to the review of Langer (Science 249: 1527-1533 (1990))

The composition may also include a granule preparation in which the active ingredient is incorporated in a polymer compound such as polylactic acid, polyglycolic acid, hydrated gel, or the like; or into a liposome, a microemulsion, a micelle, a single layer or a multi-layered bag. Body, pseudo red blood cells or spheres. The composition affects physical state, solubility, stability, in vivo release rate, and in vivo clearance.

The present invention also encompasses particulate compositions of coated polymers (e.g., polyhydroxyalkylene or Pauline) and antibody or specific tissue receptors for receptors, ligands or antigens specific for a particular tissue. A ligand-coupled compound.

The invention also includes water-soluble polymers such as polyethylene glycol, polyethylene glycol copolymers and polypropylene glycol, carboxymethyl cellulose, dextrin, polyallyl ethanol, polyethene pyrrolidone or polylysine. The valence is attached to the modified compound. It is known that the modified compound exhibits a longer half-life in blood than the corresponding unmodified compound after intravenous injection. (Abuchowski et al., 1981; Newmark et al., 1982 and Katre et al., 1987). Such modifications can also increase the solubility of the compound in aqueous solution, reduce aggregation, enhance the physical and chemical stability of the compound, and greatly reduce the antigenicity and reactivity of the compound. As a result, we have to apply a lesser or lower dose of such polymer compound exhibits than the unmodified compound to achieve the desired in vitro biological activity.

Methods of preparing a pharmaceutical composition containing the active ingredient are known to the art, for example, by mixing, granulating or forming a tablet. We usually mix the active therapeutic ingredients with excipients that are pharmaceutically acceptable or compatible with the active ingredients. When administered orally, the SARM agent or a physiologically acceptable derivative thereof such as a salt, an ester, an N-oxide, and the like is mixed with an additive conventionally used for this purpose, such as a carrier, a stabilizer, or an inert diluent. And converted to a suitable application form using customary methods, such as lozenges, coated lozenges, hard or soft gelatin capsules, aqueous, alcoholic or oily solutions. For parenteral administration, the SARM agent or a physiologically acceptable derivative thereof, such as a salt, an ester, an N-oxide, and the like, is converted into a solution, suspension or emulsion, if necessary, with customary and appropriate Substances for this purpose, such as solubilizers or others.

The active ingredient can be made into the composition as a neutralized, pharmaceutically acceptable salt form. Pharmaceutically acceptable salts include the acid addition salts thereof (formed with the free amine groups of the polypeptide or antibody molecule), which are associated with inorganic acids such as, for example, hydrochloric acid or phosphoric acid or organic acids such as acetic acid, oxalic acid, tartaric acid, almonds. The formation of acids and their analogues. The salt formed from the free carboxyl group may also be derived from an inorganic base such as sodium hydroxide, potassium, ammonium, calcium or iron with an organic base such as isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, Procaine and its analogues.

For use in medicine, the SARM salt will be a pharmaceutically acceptable salt. However, other salts may have utility in the preparation of the compounds according to the invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of the invention include acid addition salts which are obtained, for example, by mixing a solution of a compound according to the invention with a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, Aenedioic acid, maleic acid, succinic acid, acetic acid, benzylic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.

As defined herein, "contacting" means that the SARM compound of the present invention introduces a sample containing the enzyme into a test tube, flask, tissue culture, wafer, array, petri dish, microplate, capillary or the like. The SARM is allowed to combine with the enzyme for sufficient temperature and time to maintain heat. The method of contacting the sample with a SARM or other specific binding component is well known to those skilled in the art and can be selected by an analytical method. The method of holding the insulation is also standard and is known to those skilled in the art.

In another embodiment, the term "contacting" means that the SARM compound of the present invention is introduced into a patient to be treated and allows the SARM compound to be contacted with the androgen receptor in vivo.

As used herein, the term "treatment" includes prophylaxis as well as treatment for disease remission. As used herein, the terms "reduce", "repress" and "suppress" have the meaning of mitigation or reduction that we generally understand. As used herein, the term "going" means that the scope or severity increases, proceeds, grows, or deteriorates. As used herein, the term "recurring" means a response after a remission.

As used herein, the term "administering" means bringing a patient into contact with a SARM compound of the invention. As used herein, administration is accomplished in vitro, i.e., in a test tube; or in vivo, i.e., in a living organism, such as a human cell or tissue. In a specific embodiment, the invention encompasses administering a compound of the invention to a patient.

In a specific embodiment, the method of the invention comprises administering a SARM compound as a separate active ingredient. However, the scope of the present invention also includes the following methods (1) treatment of muscle wasting, (2) prevention of muscle wasting, and (3) treatment, prevention, suppression, inhibition or reduction of muscle loss due to muscle wasting, (4) Treating, preventing, inhibiting, reducing or suppressing muscle depletion caused by muscle wasting, and/or (5) treating, preventing, inhibiting, reducing or suppressing muscle protein dissimilation caused by muscle wasting, including administering A SARM compound plus one or more therapeutic agents. These agents include, but are not limited to, LHRH analogs, reversible antiandrogens, antiestrogens, selective estrogen receptor modulators (SERMS), anticancer drugs, 5-alpha reductase inhibitors, aromatase inhibitors , lutein, other selective androgen receptor modulators (SARMS), testosterone, anabolic steroids, growth hormone or agents that act via other nuclear hormone receptors.

Thus, in a specific embodiment, the invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, plus an LHRH analog. In another embodiment, the invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, plus a reversible antiandrogen. In another embodiment, the invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, plus an anti-estrogen. In another embodiment, the invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, plus a SERM. In another embodiment, the invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, plus an anti-cancer drug. In another embodiment, the invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, plus a 5-alpha reductase inhibitor. In another embodiment, the invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, plus an aromatase inhibitor. In another embodiment, the invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, plus a luteolinone. In another embodiment, the invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in addition to another SARM. In another embodiment, the invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, plus a testosterone. In another embodiment, the invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, plus an anabolic steroid. In another embodiment, the invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, plus a growth hormone. In another embodiment, the invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, plus an agent that acts via other cellular nuclear hormone receptors.

Different specific embodiments of the dosage range are covered herein. This dose range is from 0.1 to 80 mg/day. In another specific embodiment, the dosage range is from 0.1 to 50 mg/day. In another specific embodiment, the dosage range is from 0.1 to 20 mg/day. In another specific embodiment, the dosage range is from 0.1 to 10 mg/day. In another specific embodiment, the dosage range is from 0.1 to 5 mg/day. In another specific embodiment, the dosage range is from 0.5 to 5 mg/day. In another specific embodiment, the dosage range is from 0.5 to 50 mg/day. In another specific embodiment, the dosage range is from 5 to 80 mg/day. In another specific embodiment, the dosage range is from 35 to 65 mg/day. In another specific embodiment, the dosage range is from 35 to 65 mg/day. In another specific embodiment, the dosage range is from 20 to 60 mg/day. In another embodiment, the dosage range is from 40 to 60 mg/day. In another embodiment, the dosage range is from 45 to 60 mg/day. In another embodiment, the dosage range is from 40 to 60 mg/day. In another embodiment, the dosage range is from 60 to 120 mg/day. In another embodiment, the dosage range is from 120 to 240 mg/day. In another embodiment, the dosage range is from 40 to 60 mg/day. In another specific embodiment, the dosage range is from 240 to 400 mg/day. In another embodiment, the dosage range is from 45 to 60 mg/day. In another embodiment, the dosage range is 15-25 mg/day. In another embodiment, the dosage range is 5-10 mg/day. In another specific embodiment, the dosage range is from 55 to 65 mg/day. In another specific embodiment, the dosage is 20 mg/day. In another specific embodiment, the dosage is 40 mg/day. In another specific embodiment, the dosage is 60 mg/day.

The following examples are presented to more fully illustrate some specific embodiments of the invention. However, it should not be construed as limiting the invention in any way.

Experimental detail Example 1 Effect of Selective androgen Receptor Regulator (SARMS) and Cholesterone on Complete Female Rat Skeletal Muscle

Compound V (N-[4-Nitro-3-trifluoromethyl)phenyl]-(2S)-3-[4-(ethylideneamino)phenoxy]-2-hydroxy-2-methyl Selective androgen receptor modulators of the formula:

Compound V is an AR ligand with strong binding affinity, which exhibits tissue-selective androgen and assimilation effects, and has an oral form. Compound V is a potent assimilating agent that maintains the quality of the levator muscle of castrated male rats.

Myosin heavy chain (MHC) is a dominant protein encoded by a multi-gene family in skeletal muscle that is expressed in a tissue-specific and epigenetically regulated manner. [Adams G.R., Zeng S.A., Baldwin K.M. Am. J. Physiol. 276: R954-R961, 1999]. To further illustrate the importance of Compound V for muscle, we used RT-PCR to detect the performance of MHC subtypes to illustrate the effect of this non-steroidal assimilation agent on skeletal muscle. At the stationary phase, the performance of the mRNA is usually consistent with the MHC protein expression pattern. Because the transcription of MHC mRNA occurs before MHC protein translation, and the sensitivity of RT-PCR sensitization to Western blotting is rapidly detectable in mRNA expression, and can be used to analyze the subtle dynamic effects of muscle assimilation [ Wright C., Haddad F., Qin AX, Baldwin KMJ Appl. Phys. 83(4): 1389-1396, 1997].

method:

Rat muscle tissue was harvested in 5 volumes of RNA later solution (Ambion, catalog #7020) and stored at 4 °C for RNA isolation. Total RNA was isolated by the FastPrep FP120 instrument (Qbiogene) using the RNAqueous-4 PCR kit (Ambion catalog #1914) plus a FastRNA green tube (Qbiogene, catalog #6040-600) set for 45 seconds at a speed of 6.5. Reverse translation was performed with 1 microgram of total RNA using the Retroscript kit (Ambion, catalog #1710). The mixture was incubated at 42 ° C for 60 minutes, followed by 10 minutes at 92 ° C ° C, then cooled on ice and subjected to a PCR reaction.

We used comparable quantitative RT-PCR to analyze the performance of MHC mRNA in rat muscle masticatory muscle (MM) and levator muscle (LA). We used 18S ribosomal RNA as the intrinsic standard set (the typical 18S intrinsic standard set of Quantum RNA, Ambion, catalog #1716). We determined the linear range of PCR reactions for all primers and the optimal ratio of 18S primers to competitors when achieving the same amplification for our desired genes.

The primers were purchased from IDT according to the recently published design (Wright et al., J. Appl. Phys. 1997; 83: 1389), and the sequence is as follows: 5'GAAGGCCAAGAAGGCCATC3'.

In order to design a perfect match with the upstream primer of the new sequence, the above general primer must be slightly modified (Table 1). However, the optimum adhesion temperature of these general degenerate primers is constant and is used in the same manner as a general primer for the PCR reaction of 5'-oligonucleotide acid. The 3'-oligonucleotide acid used in the PCR reaction was designed for use in the untranslated region of each of the different MHC genes, and its sequence is highly specific for each MHC gene [Wright et al. 1997]:

5 units of Taq DNA polymerase (Roche, catalog #1146165), 200 microliters of each dNTP (Invitrogen, catalog #R725-01), each 0.2 micromolar concentration of MHC were used in a 50 microliter PCR reaction. The primer (IDT), 1 microliter of cDNA derived from the reverse transcription reaction and 4 microliters of 18S primer: plus a competitor mixture. The reaction was carried out in a PTC-100 Programmable Thermal Controller (MJ Research, Inc.), and the initial denaturation step was 94 ° C for 3 minutes, followed by an optimal round reaction of the MHC primer pair, each reaction including 94 ° C, 45 seconds, 48 ° C, 60 seconds, 72 ° C, 90 seconds and the final step was 72 ° C, 5 minutes. Analysis by agarose gel electrophoresis [20 μl of an equivalent amount of 50 μl of PCR reaction product loaded on 1.5% agarose gel (1× Tris-Acetate-EDTA buffer) containing 0.2 μg/ml ethidium bromide] to observe the PCR product . The agarose gel was photographed under ultraviolet (UV) using Polaroid Immediate Development Film No. 57. Scan the photo and determine the amount of optical density (OD) of the DNA band with Image Quant software (Moleclar Dynamics) and subtract the background (thus, the local background is directly proportional to the amount of DNA widely available). The intensity of the MHC band (the amount of OD) is divided by the intensity of the control fragment, thereby correcting for differences in efficiency in any PCR reaction. The amount of the MHC gene population for each experiment was calculated as a percentage of the MHC value in the control group (Table 2).

result:

We set the chewing muscle cut out from the untreated intact female rats to the control amount (referred to as the histogram of Figure 1a) of the MHC IIb expression (indicating 100%). The effect of MHC IIb treatment on the masticatory muscles was compared between the male and female treated male and the untreated control. The results showed that the testosterone propionate had a positive effect on the chewing muscle, which increased the transcription of MHC class IIb by 142% compared to the untreated control group (Fig. 1b). Compound V was found to have a similar effect, which increased MHC IIb transcription by 124% (Fig. 1b). Figure 1a shows the true untransformed data (PCR results).

In these same rats we dissected the levator muscle and assessed the phenotype of the MHC family members. The data show that all animals treated with androgen (TP or Compound V) for 14- to 28-day period have muscles in the musculature position we expect, and the characteristics of the tissue are determined by PCR to show the presence of MHC IIb. A very small number of MHC IIx subtypes and the same as the newborn. SDS-PAGE and immunostaining reactions of MHC class II specific antibodies showed a band with a distinct molecular weight of approximately 200 kDa. These results are consistent with the appearance of levator muscle. [Talmadge R.J. and Roy R.R.J. Appl. Physiol. 75(5): 2337-2340, 1993].

In a similar experiment with the chewing muscle and the gastrocnemius muscle, the chewing muscle and the gastrocnemius muscle line dissected from the intact male rats were used as a control group (Fig. 2) of MHC gastrocnemius IIb (Fig. 2) (indicating 100%). We compared the effects of male and female hormone-treated intact male and untreated controls on MHC IIb in the mastic and gastrocnemius muscles. The results showed that decyl ketone propionate had a positive effect on the chewing muscle, which increased the transcription of MHC class IIb by 120 (± 14)% compared to the untreated control group (Fig. 2 - top). Compound V also has an assimilation effect on muscle, which increases MHC IIb type by 117 (±13)% (Fig. 2 - top). Similar results were seen in the gastrocnemius. The testosterone propionate has a positive effect on the gastrocnemius muscle, which increases the transcription of MHC class IIb by 139 (±47)% compared to the untreated control group (Fig. 2 - bottom). Compound V also has an assimilation effect on muscle, which increases MHC IIb type by 162 (±54)% (Fig. 2 - bottom).

in conclusion:

These results show that the selective androgen receptor modulator (SARM), exemplified by compounds V and TP, has a direct assimilation effect on the skeletal muscle system of undissected female and male rats if measured by a net increase in MHC mRNA expression. effect. In addition, treatment with these assimilation agents for 14- or 28-day periods can result in levator hypertrophy. A few decades ago, we confirmed that testosterone is an assogenic male hormone. Shown herein are oral bioavailable non-steroidal agents, such as the selective androgen receptor modulator (SARM) exemplified by Compound V, which have tissue-selective assimilation effects on male rats, which increase muscle mass. The selective androgen receptor modulator (SARM) as described above is used to treat diseases or conditions such as dissimilation syndromes of poor muscle disease associated with aging or chronic diseases and female sexual dysfunction.

Example 2 Pharmacological activity and tissue selectivity of compound V or VI against rats of different hormonal status

Previous studies by applicants have shown that Compound V is a potent and potent selective androgen receptor modulator (SARM) for castrated male rats. To provide a representative model of a large number of males who may actually be treated with this agent, the applicant completed a pharmacological study of Compound V, Compound VI, another potent SARM and steroidal propionate (TP) in male rats of different hormonal status. Preclinical studies of efficacy and tissue selectivity. We included male rats with normal testicular function (i.e., intact without surgical resection) to examine the effect of Compound V on animals with normal blood steroid levels. We included male rats who underwent unilateral sacral resection (ie, surgical removal of one sputum) to examine the effect of Compound V on animals with slightly reduced androgen. We included male rats who underwent bilateral splenectomy (ie, surgical removal of all two testicles) to examine the effects of Compound V and VI on androgen-deficient animals.

method:

Compound V and VI were synthesized and characterized by Dr. Duane Miller at the University of Tennessee, Menphis, TN, USA. Male Sprague-Dawley rat lines were purchased from Harlen Biosciences (Indianapolis, IN). We allowed the animal to receive an unrestricted 12-hour cycle of light and darkened food and water. All animal studies were reviewed and approved by the Animal Care and Use Committee of The Ohio State University and followed by the Principles of Laboratory Animal Care (NIH Bulletin #85-23, revised 1985). We divided the juvenile male Sprague-Dawley rats weighing 187-214 g into 9 groups, 5 in each group. One day before the start of drug treatment, the 4th to 6th groups and the 7th to 9th groups were treated with a midline incision of the scrotum to receive unilateral and bilateral sacral resection. All of the drugs for the animals were freshly prepared as a solution of polyethylene glycol 300 (PEG 300). Groups 4 and 7 were treated with vehicle alone. We administered steroidal propionate (TP, 0.5 mg/day) to animals in groups 3, 6 and 9 implanted subcutaneous osmotic pressure pump (Model 2002, Durect Corporation, Palo Alto, CA). We implanted subcutaneous osmotic pressure pumps in groups 2, 5 and 8 with compound V or compound VI (0.5 mg/day). After 14 days of drug treatment, the rats were weighed, anesthetized and slaughtered. Cut the prostate back, seminal vesicles and levator muscles and weigh them separately. The robot removes the osmotic pressure pump to see if it is operating correctly. All organs were normalized to their body weight and analyzed by a single factor ANOVA and alpha values a priori at p < 0.05, and any statistically significant differences between the groups were analyzed. The weight of the prostate and seminal vesicles is used as an indicator of the activity of androgen, and the weight of the levator is used to assess the assimilation activity. When statistical analysis can be performed using parameters of the complete blood count or serum chemistry description, the single factor ANOVA and the alpha value are a priori set at p < 0.05.

result:

As shown in Table 3 and Figure 3, in intact animals, Compound V reduced the size of the prostate by 79%, and animals in the control group also observed the same results (Fig. 3A); there was no statistical difference in the size of the seminal vesicles (Fig. 3) 3B), there is no difference in levator muscle (Fig. 3C). The pharmacological effect and tissue selectivity of Compound V on animals excised from one testicle were more obvious. (Table 3 and Figure 4). We observed that compound V reduced the size of the prostate (Fig. 4A) and seminal vesicle (Fig. 4B) by 75% and 79%, respectively, and increased the levator size (Fig. 4C) by 108% compared with untreated unilateral testicular resected animals. . These observations show that Compound V is a partial agonist of the prostate and seminal vesicles and acts as a full agonist of the levator muscle. No negative pharmacological effects were observed. As shown in Table 3 and Figures 5 and 6, similar results were observed in castrated animals.

Table 4 shows the comparison of androgen and assimilation activities of Compound V with Compound VI.

in conclusion:

Compound V showed potent and tissue selective pharmacological effects in intact male rats with unilateral pill resection and castration. Compound V caused a significant reduction in prostate weight in intact and unilateral pill resected animals and was less effective than TP in increasing the prostate weight of castrated animals. A similar pharmacological activity is also observed in the case of the seminal vesicle (another organ usually considered to be the marker of the androgen effect), with the exception that the compound V has no effect on the seminal vesicle weight of the intact animal. These effects are greater than those observed by the TP. These data show the tissue selective pharmacological effects of Compound V. It is important to understand that these effects were observed when there was no significant change in plasma concentrations of FSH, LH, and testosterone (not present). In other words, these data indicate that Compound V exhibits optimal pharmacological conditions in male animals, and we can confirm that it is the first member of a new class of oral bioavailable and tissue-selective SARMs.

Example 3 Pharmacological Activity and Tissue Selectivity of Selective Androgen Receptor Regulators with Selective Halogenation in Rats

The compound VI-X of Table 5 was synthesized and characterized by Dr. Duane Miller at the University of Tennessee, Memphis, TN.

The tissue selectivity and pharmacological activity of Compound VI-X were determined as in Example 2 above.

Table 5 shows the chemical structures and binding affinities of the compounds VI-IX. Binding affinity lines are determined as described by He et al. Eur. J. Med. Chem. (2002), 619-634 and Mukherjee et al. Xenobiotica (1996) 26, 117-122.

result:

As shown in Figure 7, compound VI-IX showed tissue selectivity and pharmacological activity in castrated male rats, and higher efficiency in assimilation tissues (ie, levator muscle) compared with androgen tissue (ie, prostate and seminal vesicle). . All compounds VI-IX have an assimilation effect, and the weight of the levator is increased in a dose-dependent manner. Compounds VI, VIII, and IX (Figures 7A, C, and D, respectively) increased the weight of the levator near the intact control group. The effect of Compound VII (Fig. 7B) was more pronounced - increasing the weight of the levator muscle over the intact control group. There were no statistically significant differences in prostate and seminal vesicle size. These data show the tissue selective pharmacological activity of compound VI-IX.

Example 4 Pharmacological activity and tissue selectivity of compound X in rats

Compound X (Table 6) was synthesized and characterized by Dr. Duane Miller at the University of Tennessee, Memphis, TN.

The tissue selectivity and pharmacological activity of Compound X were determined as in Examples 2 and 3 above.

Table 6 shows the chemical structure and binding affinity of Compound X. The binding affinity is determined as described by He et al.

result:

As shown in Table 7 and Figure 8, Compound X showed tissue-selective pharmacological activity against castrated male rats, and higher assimilation tissue (ie, levator muscle) compared with androgen tissue (ie, prostate and seminal vesicle). effectiveness. Compound X showed low pharmacological activity against the prostate (8.7 ± 1.39% at 1.0 mg/day for the intact) and seminal vesicle (10.7 ± 0.91% at 1.0 mg/day for the intact), meaning that for these The tissue has a weak partial kinetin effect. Importantly, Compound X had a high efficiency of assimilation activity at a dose of 1.0 mg/day, and the return levator was 75.2 ± 9.51% of the observed value of the intact animal.

Pharmacological Activity and Tissue Selectivity of Compounds XI and XII of Example 5 in Rats

Compounds XI and XII (Table 8) were synthesized and characterized by Dr. Duane Miller at the University of Tennessee, Memphis, TN.

The tissue selectivity and pharmacological activity of Compounds XI and XII were determined as in Examples 2 to 4 above.

Table 8 shows the chemical structures and binding affinities of compounds XI and XII. The binding affinity is determined as described by He et al.

result:

As shown in Table 9 and Figure 9, the compounds XI and XII showed tissue-selective pharmacological activity against castrated male rats, and compared with the androgen tissue (ie, prostate and seminal vesicle), the assimilation tissue (ie, levator muscle) was compared. high efficiency. Compound XI is part of the pharmacological activity of the prostate (33.1 ± 8.5% in the intact at 1.0 mg / day dose) and the seminal vesicle (23.6 ± 8.8% in the intact at 1.0 mg / day), meaning that it is As a weak part of these organizations. Importantly, Compound XII showed a high efficiency of assimilation activity at a dose of 1.0 mg/day, and the return levator was 112.8 ± 9.4% of the observed value of the intact animal (daily injection) and the observed value of the intact animal was 122.5 ± 10.4% (gang). Compound XII has a low pharmacological activity against the prostate (7.2 ± 1.4% at 1.0 mg/day for the intact) and seminal vesicle (7.2 ± 0.9% at 1.0 mg/day for the intact), meaning that it is As a weak part of these organizations. Importantly, Compound XII showed an assimilation activity at a dose of 1.0 mg/day, returning levator muscle to 55.83 ± 2.84% of the observed value of intact animals.

^* Reference group treated by infiltration pump with 1 mg/day GTx02-CK2-1

It should be understood by those skilled in the art that the present invention is not limited to the specific examples and descriptions described above. Moreover, the scope of the invention is defined by the scope of the following claims.

Figure 1: Effect of androgen on the expression of MHC II b mRNA in the masticatory muscle of female rats. (A) Analysis of 1.2% agarose gel of MHC II b (590 base pair) with internal control by 18S mRNA (488 base pair); (B) Control group (C, no drug treatment), steroidal propionate ( Histogram analysis of TP) and compound V.

Figure 2: Effect of steroidal propionate and compound V on myosin heavy chain (MHC) IIb mRNA expression. Whole male Sprague-Dawley rats were treated with placebo, ketal propionate (5 mg/kg/day) or Compound V (1 mg/kg/day), respectively. The histogram shows the effect of Compound V on the expression of MHC IIb mRNA in the chewing muscle (top) and gastrocnemius (bottom).

Figure 3: Activity of compounds V and VI on androgen and catabolism in rats. Male rats with normal testicular activity (untreated) were divided into untreated (intact), treated with Compound V (0.5 mg/day), treated with Compound VI (0.5 mg/day) or treated with dextran propionate (TP, 0.5 mg/day) and the weight of the androgen-reactive tissue (prostate - Figure 3A, seminal vesicle - Figure 3B and levator - Figure 3C).

Figure 4: Activity of compounds V and VI on androgen and catabolism in rats. Male rats undergoing unilateral sacral resection (half sacral resection) were divided into untreated (intact), treated with vehicle alone (PEG 300), treated with compound V (0.5 mg/day), treated with compound VI ( 0.5 mg/day), or treated with guanosterone propionate (TP, 0.5 mg/day) and determined for androgen-reactive tissue (prostate - Figure 4A, seminal vesicle - Figure 4B and levator - Figure 4C) weight.

Figure 5: Activity of compounds V and VI on androgen and catabolism in rats. Male rats undergoing bilateral splenectomy (castration) were divided into untreated (intact), treated with vehicle alone (PEG 300), treated with compound V (0.5 mg/day), treated with compound VI (0.5 mg/ Days, or the weight of the androgen-reactive tissue (prostate - Figure 5A, seminal vesicle - Figure 5B and levator - Figure 5C) treated with decyl ketone propionate (TP, 0.5 mg / day).

Figure 6: Curve of reaction dose. The rats were treated untreated or treated with 0.1, 0.3, 0.5, 0.75 and 1.0 mg/day of Compound V, Compound VI or steroidal propionate (TP) and the androgen-reactive tissue (prostate - Figure 6A, the weight of the seminal vesicle - Figure 6B and levator - Figure 6C). Results are expressed as a percentage of the intact control group.

Figure 7: Dose response curve of compound VI-IX in rats. The rats are treated untreated or treated with 0.1, 0.3, 0.5, 0.75 and 1 mg/day of compound VI (A), compound VII (B), compound VIII (C) or compound IX (D), and paired The weight of the androgen-reactive tissue (prostate and seminal vesicle) and levator muscle.

Figure 8: Dose response curve of Compound X in rats. Castrated rats were treated untreated (control group) or treated with 0.1, 0.25, 0.5, 0.75 and 1 mg/day of compound X, and the androgen-reactive tissues (prostate and seminal vesicle) and levator muscle were determined. weight. Complete representation of male rats with normal testicular function (untreated).

Figure 9: Activity of compounds XI and XII on androgen and catabolism in rats. Male rats undergoing bilateral splenectomy (castration) were divided into untreated (castration control group), or treated with compound XI at 1 mg/day and compound XII, and the androgen-reactive tissues (prostate and seminal vesicle) were determined. With the weight of the levator. Complete representation of male rats with normal testicular function (untreated).

(no component symbol description)

Claims (18)

A pharmaceutical composition for treating a muscle depletion caused by cancer in a patient, comprising a selective androgen receptor modulator (SARM) compound having the structure of formula I or an isomer or pharmaceutically acceptable salt thereof: Wherein G is O; X is O; T is OH or OR; Z is NO ₂ , CN, COOH, COR, NHCOR or CONHR; Y is CF ₃ , F, I, Br, Cl or CN; Q is an alkyl group, Halogen, CF ₃ , CN, C(R) ₃ , Sn(R) ₃ , N(R) ₂ , NHCOCH ₃ , NHCOCF ₃ , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH ₃ , NHCSCF ₃ , NHCSR, NHSO ₂ CH ₃ , NHSO ₂ R, OR, COR, OCOR, OSO ₂ R, SO ₂ R or SR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CF ₃ , aryl, phenyl, halogen, alkenyl or OH; and R ₁ is CH ₃ , CH ₂ F, CHF ₂ , CF ₃ , CH ₂ CH ₃ or CF ₂ CF ₃ . The pharmaceutical composition according to claim 1, wherein the SARM compound has the structure of formula II: Wherein X is O; Z is NO ₂ , CN, COOH, COR, NHCOR or CONHR; Y is CF ₃ , F, I, Br, Cl or CN; Q is alkyl, halogen, CF ₃ , CN, C (R ₃ , Sn(R) ₃ , N(R) ₂ , NHCOCH ₃ , NHCOCF ₃ , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH ₃ , NHCSCF ₃ , NHCSR, NHSO ₂ CH ₃ , NHSO ₂ R, OR, COR, OCOR, OSO ₂ R, SO ₂ R or SR; and R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CF ₃ , aromatic a phenyl group, a halogen, an alkenyl group or an OH; or an isomer thereof or a pharmaceutically acceptable salt thereof. A pharmaceutical composition according to claim 2, wherein Y is CF ₃ . A pharmaceutical composition according to claim 2, wherein Z is NO ₂ . A pharmaceutical composition according to claim 2, wherein Z is CN. The pharmaceutical composition according to claim 2, wherein Q is a halogen. A pharmaceutical composition according to claim 2, wherein Q is NHCOCH ₃ . The pharmaceutical composition according to claim 2, wherein Z is NO ₂ , Y is CF ₃ and Q is a halogen. The pharmaceutical composition according to claim 2, wherein Z is NO ₂ , Y is CF ₃ and Q is NHCOCH ₃ . The pharmaceutical composition according to claim 2, wherein Z is CN, Y is CF ₃ and Q is halogen. The pharmaceutical composition according to claim 2, wherein Z is CN, Y is CF ₃ and Q is NHCOCH ₃ . A pharmaceutical composition according to claim 1 of the patent application, comprising the SARM compound or an isomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 12, which is administered intravenously, intra-arterially or intramuscularly in a liquid form; contained in a tablet and implanted under the skin of a patient; orally administered to a patient in a liquid or solid form; or partially Apply to the skin surface of the patient. The pharmaceutical composition according to claim 12, wherein the pharmaceutical composition is a tablet, a tablet, a capsule, a solution, a suspension, an emulsion, an elixir, a gel, a cream, a suppository or a parenteral formulation. The pharmaceutical composition according to claim 1, wherein the compound has the structure of formula X: The pharmaceutical composition according to claim 15 of the patent application, comprising the SARM compound or an isomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 16 of the patent application, which is administered intravenously, intra-arterially or intramuscularly in a liquid form; contained in a tablet and implanted under the skin of a patient; orally administered to a patient in a liquid or solid form; or partially Apply to the skin surface of the patient. The pharmaceutical composition according to claim 16, wherein the pharmaceutical composition is a tablet, a tablet, a capsule, a solution, a suspension, an emulsion, an elixir, a gel, a cream, a suppository or a parenteral formulation.