CN102976973B - SARM and using method thereof - Google Patents

SARM and using method thereof Download PDF

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CN102976973B
CN102976973B CN201210510464.8A CN201210510464A CN102976973B CN 102976973 B CN102976973 B CN 102976973B CN 201210510464 A CN201210510464 A CN 201210510464A CN 102976973 B CN102976973 B CN 102976973B
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sarm
bone
compound
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CN102976973A (en
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詹姆斯·T.·多尔顿
杜安·D.·米勒
卡伦·A.·韦韦尔卡
J·金
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University of Tennessee Research Foundation
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University of Tennessee Research Foundation
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Priority claimed from US10/861,923 external-priority patent/US8008348B2/en
Priority claimed from US10/863,524 external-priority patent/US20050038110A1/en
Priority claimed from US10/961,380 external-priority patent/US20060019931A1/en
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Priority claimed from CN 200580018468 external-priority patent/CN1964712A/en
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Abstract

The present invention relates to SARM and using method thereof.Specifically, the invention provides SARM compound and the application in treatment individuality in various diseases or illness thereof, described disease or illness particularly comprise wasting disease or illness or bone related disease or illness.

Description

SARM and using method thereof
The application submits on June 7th, 2005, and denomination of invention is the divisional application of the Chinese patent application 200580018468.2 of " SARM and using method thereof ".
Background technology
Androgen receptor (" AR ") is the transcription regulatory protein of ligand activation, and it mediates the induction of male sexual development and function by its endogenous androgens activity.Male sex hormone is commonly called male sex hormone.Male sex hormone is produced in vivo by testis and adrenal cortex, or the steroid that can synthesize in the lab.Androgenic steroids plays an important role in many physiological processs, comprise male sex characteristics as the growth of muscle and bone amount and maintenance, prostatic growth, spermatogenesis and male sex's hair distribution (Matsumoto, Endocnnol.Met.Clin.N.Am.23:857-75 (1994)).Endogenous steroidal androgens comprises testosterone and dihydrotestosterone (" DHT ").Testosterone is by the major steroid of testicular secretion, and is the primary circulating androgen found in male sex's serum.In many peripheral tissues, testosterone is changed into DHT by enzyme 5α-reductase.Therefore think, for most of androgenic effect, DHT plays a part medium in born of the same parents (people such as Zhou, Molec.Endocrinol.9:208-18 (1995)).Other Steroidal androgens comprises the ester of testosterone, as cipionate, propionic ester, phenylpropionic acid ester, cyclopentanepropanoiacid acid ester, isocarporate, heptanoate and decylate, and other synthetic androgen, as 7-methylnortestosterone (" MENT ") and the acetic ester (people such as Sundaram thereof, " 7Alpha-Methyl-Nortestosterone (MENT): The OptimalAndrogen For Male Contraception; " Ann.Med, 25:199-205 (1993) (" Sundaram ")).Because AR participates in male sexual development and function, so AR is likely the target of the hormone replacement therapy realizing male contraception or other form.
The BMD (bone mineral density) of masculinity and femininity all reduces with the growth at age.The slippage of bone mineral content (BMC) and BMD and bone strength reduce and have dependency, make patient be easy to fracture.
Osteoporosis is a kind of systemic skeletal disease, it is characterized by Low BMD, osseous tissue is degenerated, and result makes bone fragility increase and is easy to fracture.In the U.S., there is the people of more than 2,500 ten thousand to suffer from this illness, cause more than 130 ten thousand example fracture every year, comprising annual 500000 routine non-spine fractures, 250000 routine hip fractures and 240000 routine fracture of the carpal bone.Hip fracture is osteoporosis severest consequences, cause every year the individual death of 5-20%, more than 50% survivor maimed.It is maximum that the elderly suffers from osteoporotic risk, therefore estimates along with this problem of aging population is more and more serious.The sickness rate of whole world fracture is estimated by increase by three times in next 60 years, and research estimation the year two thousand fifty whole world hip fracture number will have 4,500,000 examples.
The osteoporotic risk of women is greater than the male sex.Women's bone lesion in post menopausal 5 years obviously accelerates.Other factor increasing this risk comprises smoking, alcohol abuse, the mode of life of sitting and low calcium and takes in.But also often there is osteoporosis in the male sex.Clearly determine that male sex's bone mineral density increases with the age and reduces.Bone mineral content reduces relevant with the minimizing of amount of densities with bone strength, and is easy to fracture.The molecule mechanism of sexual hormoue pleiotropic effects in non-germinal tissue has just started to be familiar with, but male sex hormone and estrogenic physiological concentration to play an important role to maintenance bone stable state in whole life cycle be clearly.Therefore, when male sex hormone or estrogen deprivation occur, consequently bone remodeling speed increases, and the counterbalancing tiit of absorption and formation is absorbed for being conducive to, and this causes overall bone amount to be lost.In the male sex, the minimizing (androgenic direct minimizing and the lower estrogen level derived from androgenic periphery aromizing) naturally of maturity hormone is relevant with bone fragility.This effect is also observed in the castrating male sex.
Muscle wasting disorder refers to muscle mass progressive loss and/or muscle, comprises skeletal muscle or voluntary muscle, the cardiac muscle (myocardosis) of control heart and the gradual unable of unstriated muscle of controls movement and degenerates.Chronic muscular marasmus is chronic disease (namely continuing a rapid lapse of time), it is characterized in that the progressive loss of muscle mass, the unable and degeneration of muscle.
The feature of the loss of muscle mass occurred during muscle wasting disorder can be muscle protein breakdown degraded.The reason that breaks down proteins occurs is unusual high protein degradation speed, unusual low protein synthesis rate, or the combination of the two.No matter muscle protein degradation, be caused by high protein degree of degradation or caused by lower protein synthesis degree, all cause muscle mass to reduce and cause muscle wasting disorder.
Muscle wasting disorder is relevant with chronic, nervosa, heredity or infectivity pathology, disease, slight illness or illness.These comprise muscular dystrophy, as bulbar paralysis muscular dystrophy and myotonia atrophica; Myatrophy, as Post-Polio Muscular Atrophy (PPMA); Emaciation, as Cardiac cachexia, AIDS emaciation and cancer cachexia, malnutrition, leprosy, diabetes, ephrosis, chronic obstructive pulmonary disease (COPD), cancer, end stage Renal failure, Sarcopenia (sarcopenia), pulmonary emphysema, osteomalacia, HIV, AIDS and myocardosis.
In addition, other environment is relevant with muscle wasting disorder with illness, and can cause muscle wasting disorder.These comprise chronic lower back pain, advanced age, central nervous system (CNS) damage, peripheral nerve injury, Spinal injury, chemical damage, central nervous system (CNS) infringement, peripheral lesion, spinal cord lesion, chemical damage, burn, causing four limbs to be fixed due to ailing or damage, long-term inpatients time the useless sexual function that occurs degenerate (disuse deconditioning), and alcoholism.
Complete androgen receptor (AR) signal pathway plays a crucial role for the appropriate development of skeletal muscle.And complete AR-signal pathway increases thin heavy, the muscular strength of muscle and myoprotein synthesis.
If the unabated words of muscle wasting disorder, may have fearful health consequences.Such as, the change occurred during muscle wasting disorder may cause physical appearance to die down, and this is harmful to the health of individuality, cause to infect susceptibility increase and behavior state bad.In addition, muscle wasting disorder is the strong predictor suffering from emaciation and AIDS patient morbidity and mortality ratio.
Basic science level and clinical level a kind of be all badly in need of initiative method is with prevention and therapy osteoporosis and other bone-related disorder and muscle wasting disorder, particularly chronic muscular marasmus.The present invention meets this needs.
Summary of the invention
In one embodiment, the invention provides a kind of SARM (SARM) compound of being represented by the structure of formula (I) or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination:
Wherein X is O;
Z is NO 2, CN, COR or CONHR;
Y is I, CF 3, Br, Cl, F or Sn (R) 3;
Q is CN;
T is OH, OR ,-NHCOCH 3, NHCOR or OC (O) R;
R is alkyl, haloalkyl, dihalo alkyl, tri haloalkyl, CH 2f, CHF 2, CF 3, CF 2cF 3, aryl, phenyl, halogen, thiazolinyl or OH; And
R 1for CH 3, CH 2f, CHF 2, CF 3, CH 2cH 3or CF 2cF 3.
In another embodiment, the invention provides SARM (SARM) compound represented by the structure of formula (III) or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination:
In another embodiment, the invention provides SARM (SARM) compound represented by the structure of formula (IV) or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination:
Wherein X is O;
T is OH, OR, NHCOCH 3, NHCOR or OC (O) R;
Z is H, alkyl, NO 2, CN, COOH, COR, NHCOR or CONHR;
Y is H, alkyl, CF 3, halogen, hydroxyl-alkyl or alkyl aldehydes;
A is selected from following group:
Wherein
R 2, R 3, R 4, R 5, R 6be H, halogen, CN, NO independently 2, NHCOCF 3;
R is alkyl, haloalkyl, dihalo alkyl, tri haloalkyl, CH 2f, CHF 2, CF 3, CF 2cF 3, aryl, phenyl, halogen, thiazolinyl or OH; And
R 1for CH 3, CH 2f, CHF 2, CF 3, CH 2cH 3or CF 2cF 3.
In one embodiment, according to this aspect of the invention, X is O, or in another embodiment, T is OH, or in another embodiment, R 1for CH 3, or in another embodiment, Z is NO 2, or in another embodiment, Z is CN, or in another embodiment, R 2, R 3, R 5, R 6for H, and R 4for NHCOCF 3, or in another embodiment, R 2, R 3, R 5, R 6for H, and R 4for F, or in another embodiment, R 2, R 3, R 5, R 6for H, or in another embodiment, Z in contraposition, or in another embodiment, Y in a position, or in another embodiment, their arbitrary combination.
In another embodiment, the invention provides a kind of pharmaceutical composition, it contains formula (I), the SARM compound of (III) or (IV) and suitable carrier or thinner.
In another embodiment, the invention provides formula (I), the compound of (III) or (IV) or the composition containing it and treat the application suffered from the individuality of bone-related disorder.
In another embodiment, the invention provides formula (I), the compound of (III) or (IV) or the composition containing it increasing individual bone strength or bone amount or promoting the application in individual bone forming.
In another embodiment, the invention provides formula (I), the compound of (III) or (IV) be used for the treatment of, prevent, suppress, the application suppressed in the incidence of the individual muscle wasting disorder of individual muscle wasting disorder or reduction.
In another embodiment, the invention provides formula (I), the compound of (III) or (IV) increasing the application of individual muscle behavior expression, muscle size, muscular strength or its arbitrary combination.
In another embodiment, the invention provides formula (I), (III) or (IV) compound or containing its application of composition in the treatment individual metabolism syndrome obesity of being correlated with or diabetes.
In another embodiment, the invention provides formula (I), (III) or (IV) compound or containing its composition in the application promoted or in accelerating to recover after operation technique.
In another embodiment, the invention provides formula (I), the compound of (III) or (IV) or the composition containing it promoting or suppressing the application in the spermatogenesis of male individual.
Accompanying drawing explanation
fig. 1: the effect that SARM, DHT and PTH break up to scleroblast system rat bone marrow cell.
fig. 2: SARM, DHT and PTH are to the effect of the positive multinucleated osteoclast of TRAP.
fig. 3: the femur overall loading of 3 bending methods mensuration of femur.
fig. 4:pQCT analyzes the trabecular bone mineral density of the distal femoral measured.
fig. 5: the pharmacology of compound III in intact rats.
fig. 6: the organ weight of the castrating rat of compound III process, represents with the per-cent of Intact control.* P value <0.05vs. Intact control.
fig. 7: organ weight's preservation dose-response curve of compound III in castrating rat.The E of musculus levator ani (closed triangle), prostate gland (open loop) and seminal vesicle (closed square) maxand ED 50be worth by using in sigmoid curve E maxmodel carries out nonlinear regression analysis acquisition.
fig. 8: the organ weight of the castrating rat of compound III process, represents with the complete per-cent to group.* P value <0.05vs. Intact control.
fig. 9: in castrating rat, the organ weight of compound III regenerates dose-response curve.The E of musculus levator ani (closed triangle), prostate gland (open loop) and seminal vesicle (closed square) maxand ED 50be worth by using in sigmoid curve E maxmodel carries out nonlinear regression analysis acquisition.
figure 10: the oral serum concentration-time graphic representation giving compound III in PEG300 in healthy volunteer.
figure 11: the serum concentration-time graphic representation of compound III solution vs. solid oral dosage form.
figure 12: the different dosage form of compound III is with the serum concentration-time graphic representation of 30mg administration.
figure 13: the dosage vs.AUC of oral liquid (G100401) 0-inf.
figure 14: the dosage vs.C of oral liquid max.
figure 15: in rat, the cholesterol of compound III reduces.
Embodiment
In following embodiment, for providing, the present invention being understood completely, having set forth many specific details.But it will be understood by those skilled in the art that and do not have these specific details the present invention also can be put into practice.In other cases, in order to not make the present invention be limited, known method, step and component are not described in detail.
In one embodiment, the invention provides a kind of SARM (SARM) compound of being represented by the structure of formula (I) or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination:
Wherein X is O;
Z is NO 2, CN, COR or CONHR;
Y is I, CF 3, Br, Cl, F or Sn (R) 3;
Q is CN;
T is OH, OR ,-NHCOCH 3, NHCOR or OC (O) R;
R is alkyl, haloalkyl, dihalo alkyl, tri haloalkyl, CH 2f, CHF 2, CF 3, CF 2cF 3, aryl, phenyl, halogen, thiazolinyl or OH; And
R 1for CH 3, CH 2f, CHF 2, CF 3, CH 2cH 3or CF 2cF 3.
In another embodiment, the invention provides the SARM represented by the structure of formula (II):
Wherein X is O;
Z is NO 2, CN, COR or CONHR;
Y is I, CF 3, Br, Cl, F or Sn (R) 3;
R is alkyl or OH; And
Q is CN.
In one embodiment, the invention provides SARM (SARM) compound represented by the structure of formula (III) or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination:
In another embodiment, the invention provides SARM (SARM) compound represented by formula (IV) structure or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination:
Wherein X is O;
T is OH, OR, NHCOCH 3, NHCOR or OC (O) R;
Z is H, alkyl, NO 2, CN, COOH, COR, NHCOR or CONHR;
Y is H, alkyl, CF 3, halogen, hydroxyl-alkyl or alkyl aldehydes;
A is selected from following group:
Wherein
R 2, R 3, R 4, R 5, R 6be H, halogen, CN, NO independently 2, NHCOCF 3;
R is alkyl, haloalkyl, dihalo alkyl, tri haloalkyl, CH 2f, CHF 2, CF 3, CF 2cF 3, aryl, phenyl, halogen, thiazolinyl or OH; And
R 1for CH 3, CH 2f, CHF 2, CF 3, CH 2cH 3or CF 2cF 3.
In one embodiment, according to this aspect of the invention, X is O, or in another embodiment, T is OH, or in another embodiment, R 1for CH 3, or in another embodiment, Z is NO 2, or in another embodiment, Z is CN, or in another embodiment, R 2, R 3, R 5, R 6for H, and R 4for NHCOCF 3, or in another embodiment, R 2, R 3, R 5, R 6for H, and R 4for F, or in another embodiment, R 2, R 3, R 5, R 6for H, or in another embodiment, Z in contraposition, or in another embodiment, Y in a position, or in another embodiment, their arbitrary combination.
In one embodiment, the invention provides a kind of pharmaceutical composition, it contains formula (I), (II), the compound of (III) or (IV) or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination and suitable carrier or thinner.
In one embodiment, " alkyl " refers to saturated aliphatic hydrocarbon, and it comprises straight chain, side chain and cyclic alkyl.In one embodiment, alkyl has 1-12 carbon.In another embodiment, alkyl has 1-7 carbon.In another embodiment, alkyl has 1-6 carbon.In another embodiment, alkyl has 1-4 carbon.This alkyl can be unsubstituted or is selected from following group replace by one or more: halogen, hydroxyl, carbalkoxy, amido, alkyl amido, dialkylamido, nitro, amino, alkylamino, dialkyl amido, carboxyl, sulfo-and alkylthio.
In one embodiment, " thiazolinyl " refers to unsaturated hydrocarbons, and it comprises straight chain, side chain and the cyclic group with one or more double bond.Thiazolinyl can have a double bond, two double bonds, three double bonds etc.The example of thiazolinyl is vinyl, propenyl, butenyl, cyclohexenyl etc.Thiazolinyl can be unsubstituted or is selected from following group replace by one or more: halogen, hydroxyl, carbalkoxy, amido, alkyl amido, dialkylamido, nitro, amino, alkylamino, dialkyl amido, carboxyl, sulfo-and alkylthio.
" haloalkyl " refers to alkyl defined above, and it is replaced by one or more halogen atom, in one embodiment, is replaced by F, in another embodiment, replaced by Cl, in another embodiment, replaced by Br, in another embodiment, replaced by I.
" aryl " refers to the aromatic group with at least one isocyclic aryl or heterocyclic aryl, and it can be unsubstituted or is selected from following group replace by one or more: halogen, haloalkyl, hydroxyl, carbalkoxy, amido, alkyl amido, dialkylamido, nitro, amino, alkylamino, dialkyl amido, carboxyl or sulfo-or alkylthio.The limiting examples of aromatic ring is phenyl, naphthyl, pyranyl, pyrryl, pyrazinyl, pyrimidyl, pyrazolyl, pyridyl, furyl, thienyl, thiazolyl, imidazolyl, isoxazolyl etc.
" hydroxyl " refers to OH group.It will be appreciated by those skilled in the art that when the T in compound of the present invention is OR, R is not OH.
In one embodiment, term " halogen (halo) " or " halogen (halogen) " refer to F in one embodiment, refer to Cl in another embodiment, refer to Br in another embodiment, or refer to I in another embodiment.
In one embodiment, " aralkyl " refers to the alkyl be connected with aryl, wherein alkyl and aryl as defined above.The example of aralkyl is benzyl.
In one embodiment, the invention provides SARM compound and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, impurity or crystal or its arbitrary combination.In another embodiment, the invention provides the analogue of SARM compound.In another embodiment, the invention provides the derivative of SARM compound.In another embodiment, the invention provides the isomer of SARM compound.In another embodiment, the invention provides the metabolite of SARM compound.In another embodiment, the invention provides the pharmacologically acceptable salts of SARM compound.In another embodiment, the invention provides the medicine of SARM compound.In another embodiment, the invention provides the hydrate of SARM compound.In another embodiment, the invention provides the N-oxide compound of SARM compound.In another embodiment, the invention provides the prodrug of SARM compound.In another embodiment, the invention provides the polymorphic form of SARM compound.In another embodiment, the invention provides the crystal of SARM compound.In another embodiment, the invention provides the impurity of SARM compound.In another embodiment, the invention provides the composition containing SARM compound, or in another embodiment, the combination of the analogue of SARM compound of the present invention, derivative, isomer, metabolite, pharmacologically acceptable salts, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, impurity or crystal is provided.
In one embodiment, term " isomer " includes but not limited to optically active isomer and analogue, constitutional isomer and analogue, conformer and analogue etc.
In one embodiment, term " isomer " refers to the optically active isomer comprising SARM compound.It will be appreciated by those skilled in the art that SARM of the present invention contains at least one chiral centre.Therefore, the SARM used in method of the present invention can exist with optical forms or racemic form, also can be separated into optical forms or racemic form.Some compounds can also show polymorphism.Should understand and the present invention includes any racemize, optically-active, polymorphic or stereoisomer form, or their mixture, these forms have the character being used for the treatment of androgen-related conditions as herein described.In one embodiment, SARM is pure (R)-isomer.In another embodiment, SARM is pure (S)-isomer.In another embodiment, SARM is the mixture of (R) and (S) isomer.In another embodiment, SARM is the racemic mixture containing equivalent (R) and (S) isomer.Well known in the artly how to prepare optical forms (such as by recrystallization technology resolution of racemic form, by from optically-active Material synthesis, carry out chromatographic separation by chiral synthesize or by use chiral stationary phase).
The present invention includes " pharmacologically acceptable salts " of SARM of the present invention, can use the SARM of amino replacement and organic and mineral acid in one embodiment, such as citric acid and hydrochloric acid prepare described pharmacologically acceptable salts.In another embodiment, pharmacologically acceptable salts can also by with mineral alkali as prepared by sodium-hydroxide treatment phenolic compound.In another embodiment, can by preparing the ester of phenolic compound by aliphatic series and aromatic carboxylic acid such as acetic acid and benzoic ether.
The present invention also comprises the N-oxide compound of the amino-substituent of SARM described herein.
The invention provides the derivative of SARM compound.In one embodiment, " derivative " includes but not limited to ether derivant, acid derivative, amide derivatives, ester derivative etc.In another embodiment, the present invention also comprises the hydrate of SARM compound.In one embodiment, " hydrate " includes but not limited to semihydrate, monohydrate, dihydrate, trihydrate etc.
In other embodiments, the invention provides the metabolite of SARM compound.In one embodiment, " metabolite " means any material of being produced by metabolism or metabolic process by another kind of material.
In other embodiments, the present invention also provides the medicine of SARM compound.In other embodiments, term " medicine " refers to the composition (pharmaceutical composition) being suitable for pharmaceutical application as described herein.
selective androgen conditioning agent (SARM)
SARM (SARM) is class androgen receptor target agent (ARTA), and they show short hero and the anabolic activity of the non-steroidal ligands of androgen receptor.These new promoting agents are used for the relevant illness of the various hormone of male treatment as sexual dysfunction, sexual desire reduction, erective dysfunction, hypogonadism, Sarcopenia, osteopenia, osteoporosis, cognition and mood change, depression, anaemia, alopecia, obesity, benign prostatic hyperplasia and/or prostate cancer.In addition, SARM is used for oral androgenic replacement therapy and prostate cancer imaging.In addition, SARM treats the relevant illness of various hormone as sexual dysfunction, sexual desire reduction, hypogonadism, Sarcopenia, osteopenia, osteoporosis, cognition and mood change, depression, anaemia, alopecia, obesity, endometriosis, breast cancer, uterus carcinoma and ovarian cancer for women.
As contemplated herein, the invention provides class SARM (SARM) compound.These compounds for prevention and therapy muscle wasting disorder and bone-related disorder are classified as androgen receptor agonist (AR agonist), partial agonist or androgen receptor antagonists (AR antagonist).
Receptor stimulant be bind receptor activation material.Acceptor portion agonist be bind receptor and part activation material.Receptor antagonist is bind receptor and makes it the material of inactivation.As this paper institute illustration, in some embodiments, SARM compound of the present invention has tissue selectivity effect, and such as wherein single promoting agent is agonist, partial agonist and/or antagonist, and this depends on the tissue that this receptor is expressed.Such as, SARM compound also can suppress prostata tissue by stimulated muscle tissue simultaneously.In one embodiment, be used for the treatment of and prevent the SARM of muscle wasting disorder to be agonist, therefore for combining and activating AR.In another embodiment, SARM is AR antagonist, therefore for making AR inactivation in conjunction with AR.Determine that compound of the present invention be AR agonist or the assay method of antagonist is known for a person skilled in the art.Such as, AR agonist activity can be monitored SARM compound and kept and/or stimulate the ability of the tissue containing AR as the growth of prostate gland and seminal vesicle to determine by adopting weight determination.AR antagonistic activity can suppress the ability of the growth containing AR tissue to be determined by monitoring SARM compound.
In another embodiment, SARM compound of the present invention can classify as partial AR agonist/antagonist.SARM is AR agonist in some tissues, causes AR-reactive group to transcribe increase (such as muscle anabolism effect).In other tissue, these compounds as the competitive inhibitor of testosterone/DHT to AR, to stop the agonism of endogenous androgens.In one embodiment, term SARM or SARM refer to the compound regulating estrogen receptor activity.In one embodiment, SARM is agonist, or in another embodiment, is antagonist.
In one embodiment, SARM has antagonistic activity in the sexual gland of individuality, and has agonist activity in periphery such as muscle.Just these activity are demonstrated, as illustrated in Fig. 3,4 or 5 than the effect aspect of musculus levator ani muscle tissue to the effect of prostata tissue herein.
In one embodiment, SARM compound of the present invention reversibly in conjunction with androgen receptor, or in another embodiment, irreversibly in conjunction with androgen receptor.In one embodiment, SARM compound is reversibly in conjunction with androgen receptor.In another embodiment, SARM compound is irreversibly in conjunction with androgen receptor.Compound of the present invention can containing the functional group's (such as affinity tag) making androgen receptor alkylation (i.e. covalent linkage form).Therefore, in the case, this compound irreversibly bind receptor, thus can not by steroid as endogenic ligand DHT and testosterone substitute.
In one embodiment, the adjustment of androgen receptor refers to that compound is stimulated by acceptor and arbitrary or all downstream effects of being conducted by receptor signal in another embodiment or the ability of enhancing signal conduction.
In another embodiment, the adjustment of androgen receptor refers to that compound is weakened by acceptor and arbitrary or all downstream effects of being conducted by receptor signal in another embodiment or the ability of erasure signal transduction.
In another embodiment, SARM of the present invention can interact with the homologue of androgen receptor.Term " homologue of androgen receptor " refers in structure in one embodiment, or refers to the acceptor of being functionally correlated with in another embodiment, and the adjustment of this receptor expects.SARM of the present invention can interact with estrogen receptor in one embodiment, or in another embodiment, interact with other cell surface molecule participating in route of synthesis, or in another embodiment, interact with other cell surface molecule participating in Steroidgenesis approach, or in another embodiment, interact with other cell surface molecule participating in pathways metabolism.
In one embodiment, the present invention also provides the composition containing a kind of SARM of the present invention, or in another embodiment, the composition containing multiple SARM of the present invention.
In one embodiment, described composition is pharmaceutical composition, in another embodiment, it is pill, tablet, capsule, micronization or non-micronization capsule, solution, suspensoid, emulsion, elixir, gelifying agent, emulsifiable paste, suppository or parenteral administration.
In one embodiment, micronization capsule contains the particle comprising SARM of the present invention, and wherein term used herein " micronization " refers to that particle diameter is less than the particle of 100 microns, in another embodiment, be less than 50 microns, or in another embodiment, be less than 35 microns, or in another embodiment, be less than 15 microns, or in another embodiment, be less than 10 microns, or in another embodiment, be less than 5 microns.
Described pharmaceutical composition can with any effectively, easily mode give, such as give by sending in Ink vessel transfusing (i.v.), intramuscular (i.m.), (i.n.), subcutaneous (s.c.) in nose, sublingual, oral, rectum, sheath or given by any mode (such as pin or conduit) that recombinant virus/composition can be delivered to tissue.Or topical can be expected to be applied to mucomembranous cell, uses for skin or eye.Another kind of administering mode gives through inhalation or aerosol formulation.
For giving Mammals, particularly people, expection doctor will determine actual dosage and treatments period, and described dosage and treatments period are most suitable for individuality, and may change with the age of unique individual, body weight and reaction.
In one embodiment, the composition given can be sterile solution, or in another embodiment, can be the aqueous solution or non-aqueous solution, suspension or emulsion.In one embodiment, described composition can contain propylene glycol, polyoxyethylene glycol, injectable organic ester as ethyl oleate or cyclodextrin.In another embodiment, described composition also can contain wetting agent, emulsifying agent and/or dispersion agent.In another embodiment, described composition also can containing sterilized water or other sterile injectable medium arbitrarily.
In one embodiment, composition of the present invention can comprise SARM of the present invention or its arbitrary combination and the acceptable vehicle of one or more pharmacy.
In one embodiment, " pharmaceutical composition " can refer to treat significant quantity one or more compounds of the present invention and for the suitable excipient in method of the present invention and/or carrier.In one embodiment, described composition is by the SARM of the present invention containing treatment significant quantity.In one embodiment, term " treatment significant quantity " can refer to given condition and give the amount that scheme provides therapeutic action.In one embodiment, described composition can be given by any method known in the art.
In one embodiment, composition of the present invention is mixed with oral or parenteral dosage forms, as uncoated tablets, coated tablet, pill, capsule, powder, granule, dispersion or suspensoid.In another embodiment, composition of the present invention is mixed with for intravenous administration.In another embodiment, compound of the present invention is formulated as the ointment, emulsifiable paste or the gel form that supply percutaneous dosing.In another embodiment, compound of the present invention is mixed with the aerosol or sprays that supply nasal administration.In another embodiment, composition of the present invention is mixed with liquid dosage form.The example of suitable liquid dosage form is included in water, the acceptable fat of pharmacy and oil, alcohol or other organic solvent and comprises solution in ester or suspensoid, emulsifiable paste, syrup or elixir, solution and/or suspensoid.
According to embodiment of the present invention, suitable excipient and carrier can be solid or liquid, and described type is selected based on the administration fashion used usually.Liposome also can be used for sending described composition.The example of suitable solid carrier comprises lactose, sucrose, gelatin and agar.Oral dosage form can containing suitable tackiness agent, lubricant, thinner, disintegrating agent, tinting material, seasonings, flow-induction agent and fusing agent.Such as liquid dosage form can containing suitable solvent, sanitas, emulsifying agent, suspending agent, thinner, sweeting agent, thickening material and fusing agent.Parenteral and Intravenous forms also comprise mineral substance and other material to make them and selected injection or delivery system type compatible.Certainly, also other vehicle can be used.
SARM of the present invention can give with various dosage.In one embodiment, SARM gives with the dosage of 0.1-200mg/ day.In another embodiment, the dosage of SARM is 0.1-10mg, or in another embodiment, 0.1-25mg, or in another embodiment, 0.1-50mg, or in another embodiment, 0.3-15mg, or in another embodiment, 0.3-30mg, or in another embodiment, 0.5-25mg, or in another embodiment, 0.5-50mg, or in another embodiment, 0.75-15mg, or in another embodiment, 0.75-60mg, or in another embodiment, 1-5mg, or in another embodiment, 1-20mg, or in another embodiment, 3-15mg, or in another embodiment, 30-50mg, or in another embodiment, 30-75mg, or in another embodiment, 100-2000mg.
SARM of the present invention can give with various dosage.In one embodiment, SARM gives with the dosage of 1mg.In another embodiment, SARM gives with the dosage of 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg or 100mg.
In one embodiment, as described herein, compound of the present invention and composition any method used in the present invention.In one embodiment, as skilled in the art will understand, SARM or containing its composition be applied in suppressions, compacting, increase or stimulation individuality useful in the reaction expected.In another embodiment, described composition also can contain other activeconstituents, and the application-specific that the activity of other activeconstituents described is just giving for SARM compound is useful.
In one embodiment, the invention provides ASARM compound of the present invention or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination for following application: 1) treat bone-related disorder; 2) bone-related disorder is prevented; 3) bone-related disorder is suppressed; 4) bone-related disorder is suppressed; 5) individual bone strength is increased; 5) individual bone amount is increased; 6) for suppressing osteoclast to generate.In one embodiment, described SARM compound is the compound of formula I as herein described, II, III or IV.
In one embodiment, described bone-related disorder is heredopathia, or in another embodiment, described bone-related disorder as the treatment plan of given disease result and be caused.Such as in one embodiment, SARM of the present invention is used for the treatment of bone-related disorder, described bone-related disorder as the Androgen deprivation therapy that prostate cancer given in individuality is reacted result and be caused.
In one embodiment, the invention provides SARM compound for preventing the application of bone-related disorder in individuality.In another embodiment, the invention provides SARM compound for suppressing the application of bone-related disorder in individuality.In another embodiment, the invention provides SARM compound for suppressing the application of bone-related disorder in individuality.In another embodiment, described SARM compound is the compound of formula (I), (II), (III) or (IV).In another embodiment, described SARM compound is formula (I), (II), the compound of (III) or (IV) or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination.
In one embodiment, described bone-related disorder is osteoporosis.In another embodiment, described bone-related disorder is osteopenia.In another embodiment, described bone-related disorder is that bone resorption increases.In another embodiment, described bone-related disorder is fracture.In another embodiment, described bone-related disorder is that bone is fragile.In another embodiment, described bone-related disorder is that BMD reduces.In another embodiment, the arbitrary combination that described bone-related disorder is osteoporosis, osteopenia, bone resorption increase, fracture, bone are fragile and BMD reduces.Often kind of illness all represents independent embodiment of the present invention.
In one embodiment, " osteoporosis " refers to exhaustion due to calcium and bone protein and the bone that causes attenuates and bone amount reduces.In another embodiment, osteoporosis is a kind of systemic skeletal disease, and it is characterized in that Low BMD and osseous tissue are degenerated, result bone fragility increases and is easy to fracture.In one embodiment, the bone strength of sufferers of osteoporosis face is abnormal, causes the risk of fracturing to increase.In another embodiment, osteoporosis makes the calcium of normal presence in bone and Protocollagen exhaust, causes osseous abnomalit or bone density to decline in one embodiment.In another embodiment, do not cause the minor fall of fracture under normal conditions or damage just may make to get involved in osteoporotic ostosis and fracture.In one embodiment, fracture can be the form (as hip fracture) of crackle or the form (compression fracture as backbone) of subsiding.Spine, hipbone and carpal bone are the regions of the usual generation of the fracture that osteoporosis causes, but other bony areas also can be fractured.In another embodiment, osteoporosis can cause postural change, physical abnormality and handiness to reduce without suppression.
In one embodiment, osteoporosis is caused by androgen-deprivation.In another embodiment, osteoporosis occurs with androgen-deprivation.In another embodiment, osteoporosis is primary osteoporosis.In another embodiment, osteoporosis is secondary osteoporosis.In another embodiment, osteoporosis is postmenopausal osteoporosis.In another embodiment, osteoporosis is teenager's osteoporosis.In another embodiment, osteoporosis is idiopathic osteoporosis.In another embodiment, osteoporosis is senile osteoporosis.
In another embodiment, primary osteoporosis is I type primary osteoporosis.In another embodiment, primary osteoporosis is II type primary osteoporosis.The osteoporosis of every type all represents independent embodiment of the present invention.
In another embodiment, osteoporosis and osteopenia are systemic skeletal disease, it is characterized by Low BMD and osseous tissue micro-architectural deterioration.In one embodiment, " micro-architectural deterioration " refers to that the connection that bone trabecula attenuates between (defined as follows) and bone trabecula is lost.In another embodiment, " osteoporosis " is defined as 2.5 standard deviations (SD) or lower of BMD lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 2.5SD or lower of BMC lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 2.0SD or lower of BMD lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 2.0SD or lower of BMC lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 3.0SD or lower of BMD lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 3.0SD or lower of BMC lower than Young Adults mean value.Osteoporosis or osteopenic often kind of definition all represent independent embodiment of the present invention.
In another embodiment, " osteoporosis " is defined as the 2.5SD of BMD lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 2.5SD of BMC lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 2.0SD of BMD lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 2.0SD of BMC lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 3.0SD of BMD lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 3.0SD of BMC lower than Young Adults mean value.Osteoporotic often kind of definition all represents independent embodiment of the present invention.
Evaluation osteoporosis and osteopenic method are well known in the art.Such as, in one embodiment, with densitometry measurement and with g/cm 2the BMD of the patient represented obtains " T value (T score) " compared with " normal value ", and this normal value is the mean value of the Young Adults peak bone mass of gender matched.In another embodiment, the bone loss amount of patient is obtained Z value (Z-score) compared with the expectation amount lost of others' group of the same age same sex.In another embodiment, " osteoporosis " is defined as the 2.5SD or lower of T value lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 2.5SD or lower of Z value lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 2.0SD or lower of T value lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 2.0SD or lower of Z value lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 3.0SD or lower of T value lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 3.0SD or lower of Z value lower than Young Adults mean value.
In another embodiment, " osteoporosis " is defined as the 2.5SD of T value lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 2.5SD of Z value lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 2.0SD of T value lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 2.0SD of Z value lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 3.0SD of T value lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 3.0SD of Z value lower than Young Adults mean value.Osteoporotic often kind of definition all represents independent embodiment of the present invention.
In one embodiment, term " BMD " refers to the survey calculation value of actual bone amount.The absolute magnitude of the bone measured by BMD usually and bone strength and weight capacity thereof there is dependency.As the risk that Measure blood pressure can contribute to prediction apoplexy, can predict by measuring BMD the risk that fracture occurs.
In one embodiment, BMD can survey and draw (mapping) commercial measurement by BMD.In one embodiment, the bone density of hipbone, spine, carpal bone or calcaneum can be measured by multiple technologies.The preferred method measuring BMD is dual-energy x-ray Osteodensitometry (DEXA).The BMD of this commercial measurement hipbone, front and back (AP) spine, position, side vertebra and carpal bone can be used.The measurement at arbitrary position can both predict the overall risk that fracture occurs, but is the best information of this position of prediction fracture from the information that privileged site obtains.Quantitative computer controls tomography (QCT) also for measuring the BMD of spine.See such as " Nuclear Medicine: " Quantitative Procedures " Walmer H W etc., Toronto Little, Brown & Co. publishes, the 1983, the 107-132 page; " Assessment ofBone Mineral Part 1, " J Nucl Medicine, pp1134-1141 (1984); And " BoneMineral Density of The Radius " J Nucl Medicine 26:13-39 (1985).The often kind of method measuring BMD all represents independent embodiment of the present invention.
In one embodiment, " osteopenia " refers to the 1-2.5SD of BMD or BMC lower than Young Adults mean value.In another embodiment, " osteopenia " phalanges calcification or bone density reduce.In one embodiment, all Skeletal systems having this illness contained in this term.Often kind of definition of illness disclosed by the invention or diagnostic method all represent independent embodiment of the present invention.
In one embodiment, term " fracture " phalanges breaks, and comprises fractured spinal bones and spinal bone fracture.In one embodiment, term " bone is fragile " instigates bone to be easy to occur the fragile state of fracture.
In one embodiment, described bone-related disorder SARM compound of the present invention or its combined therapy.In another embodiment, can before giving one or more SARM of the present invention, simultaneously or be supplied to other bone stimulus compound individual afterwards.In one embodiment, described bone stimulus compound can contain material that is natural or synthesis.
In one embodiment, as the skilled artisan will appreciate, described bone stimulus compound can comprise Delicious peptide (BMP), somatomedin is as Urogastron (EGF), fibroblast growth factor (FGF), transforming growth factor (TGF-α or TGF-β), insulin-like growth factor (IGF), Thr6 PDGF BB (PDGF), Shh is as Sonic hedgehog (sonic hedgehog), porcupine albumen (indian hedgehog) and desert hedgehog (desert hedgehog), hormone is as follicle stimulating hormone, Rat parathyroid hormone 1-34, parathyroid hormone-related peptide, activin, statin, frizzled albumen, frzb albumen or frazzled albumen, BMP associated proteins is as chordin and Pp63 glycophosphoproteins, cytokine is as IL-3, IL-7, GM-CSF, chemokine is as eotaxin, collagen protein, osteocalcin, osteonectin etc.
In another embodiment, the composition being used for the treatment of bone disorders of the present invention can contain one or more SARM of the present invention, one or more other bone stimulus compound and Osteogenic cells.In one embodiment, Osteogenic cells can be stem cell or progenitor cell, and it can be induced to differentiate into scleroblast.In another embodiment, described cell can be scleroblast.
In another embodiment, described individuality can be given by the nucleic acid of coding bone stimulus compound, think that it is a part of the present invention.
In one embodiment, osteoporosis of the present invention, osteopenia, bone resorption increases, fracture, bone are fragile, BMD declines and other illness or disease by hormone disturbance, destruction or unbalancely to cause.In another embodiment, these illnesss do not rely on hormone disturbance, destruction or unbalance and occur.Often kind of possibility all represents independent embodiment of the present invention.
In one embodiment, described hormone disturbance, imbalance or unbalance to comprise hormone excessive.In another embodiment, described hormone disturbance, imbalance or unbalancely comprise hormonoprivia.In one embodiment, described hormone is steroid hormone.In another embodiment, described hormone is oestrogenic hormon.In another embodiment, described hormone is male sex hormone.In another embodiment, described hormone is glucocorticosteroid.In another embodiment, described hormone is reflunomide.In another embodiment, described hormone is lutropin (LH).In another embodiment, described hormone is follicle stimulating hormone (FSH).In another embodiment, described hormone is other hormone any as known in the art.In another embodiment, described hormone disturbance, imbalance or unbalance relevant with menopause.In another embodiment, hormonoprivia is the result of the specific operation as the by product for the treatment of individual disease or illness.Such as, described hormonoprivia can be the result of losing as male sex hormone in the individuality that causes of the individual prostate cancer for the treatment of.
Often kind of possibility all represents independent embodiment of the present invention.
In one embodiment, the invention provides the application of SARM compound for increasing individual bone strength.In another embodiment, described SARM compound is the compound of formula (I), (II), (III) or (IV).In another embodiment, described SARM compound is formula (I), (II), the compound of (III) or (IV) or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination.Thus, increase individual bone strength.
In another embodiment, described individuality suffers from osteoporosis.In another embodiment, described osteoporosis is that hormone causes.
In one embodiment, the invention provides the application of SARM compound for increasing individual bone amount.In another embodiment, described SARM compound is the compound of formula (I), (II), (III) or (IV).In another embodiment, described SARM compound is formula (I), (II), the compound of (III) or (IV) or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination, or containing its composition.
In another embodiment, described individuality suffers from osteoporosis.In another embodiment, described osteoporosis is that hormone causes.In another embodiment, described individuality suffers from Sarcopenia or emaciation.In another embodiment, method of the present invention is provided for increasing individual bone amount, and described bone amount is cortex bone bone amount.In another embodiment, described bone amount is trabecular bone bone amount.In another embodiment, described bone amount is spongy bone bone amount.
In one embodiment, the invention provides the application of SARM compound for promoting bone growing.In another embodiment, described SARM compound is the compound of formula (I), (II), (III) or (IV).In another embodiment, described SARM compound is formula (I), (II), the compound of (III) or (IV) or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination, or containing its composition.
In another embodiment, described SARM compound stimulates or is enhanced to osteocyte generation.In another embodiment, described SARM compound suppresses osteoclast proliferation.
In one embodiment, the invention provides through the osteogenesis that scleroblast stimulates or enhancing is bred.In one embodiment, term " scleroblast " refers to participate in osteogenetic cell.In one embodiment, participating in osteogenetic scleroblast can formative tissue, and mineral deposit wherein, makes bone have intensity.In another embodiment, the invention provides the osteogenesis through suppressing osteoclast induction, or in another embodiment, provide the osteogenesis through suppressing osteoclast activity.In one embodiment, term " osteoclast " refers to the cell participating in bone remoulding, particularly bone resorption.
In one embodiment, osteopathia or illness are treated through stimulating osteogenesis by method of the present invention.In another embodiment, treatment of the present invention provides maintenance bone amount.Bone amount is kept by the balance formed between the osteoblastic activity of bone and the activity of osteoclastic osteoclast.In one embodiment, Compounds and methods for of the present invention provides the method keeping described balance.
Fig. 1-2 has set forth described SARM compound III inducing bone marrow cell to osteoblastic differentiation, and suppresses osteoclast to be induced, and shows the direct effect of SARM to scleroblast and osteoclast, and it is useful in increase sufferers of osteoporosis face bone amount.
In one embodiment, the invention provides SARM compound of the present invention or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination for following application: 1) treat muscle wasting disorder; 2) muscle wasting disorder is prevented; 3) treat, prevent, suppress, suppress or reduce the muscle caused by muscle wasting disorder to reduce; 4) treat, prevent, suppress, reduce or suppress the wasting caused by muscle wasting disorder; And/or 5) treat, prevent, suppress, reduce or suppress the mytolin katabolism caused by muscle wasting disorder.In one embodiment, described SARM compound is the compound of formula as herein described (I), (II), (III) or (IV).In another embodiment, the invention provides containing the composition for the SARM compound of the present invention of methods described herein.
In one embodiment, the invention provides the application that SARM compound is used for the treatment of the individuality suffering from muscle wasting disorder.In another embodiment, described SARM compound is the compound of formula (I), (II), (III) or (IV).In another embodiment, described SARM compound is formula (I), (II), the compound of (III) or (IV) or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination, or containing its composition.Thus treatment suffers from the individuality of muscle wasting disorder.
In another embodiment, the application that SARM compound is used for the treatment of the individuality suffering from muscle wasting disorder comprises the pharmaceutical composition given containing SARM compound.In another embodiment, give step to comprise the described pharmaceutical composition intravenously of liquid form, intra-arterial or intramuscularly to described individuality; Piller containing described pharmaceutical composition is implanted subcutaneously in described individuality; Described individuality is given by the described drug composition oral of liquid or solid form; Or described pharmaceutical composition is locally applied to the skin surface of described individuality.
Muscle is the body tissue played a role mainly as source of strength.There is the muscle of three types in vivo: a) skeletal muscle-be responsible for the end of mobile body and the muscle of external region; B) cardiac muscle-cardiac muscle; The muscle of c) unstriated muscle-in arterial wall and intestines wall.
The illness that wasting disease or illness are defined as and are characterised in that abnormal, gradual health at least partly herein, organ or tissue's weight reduces or disease.Illness of becoming thin can as pathology, and the result as cancer or infection occurs, or it exists due to physiology or metabolism state, and the useless sexual function as fixed generation due to long-term bed or four limbs is degenerated.Illness of becoming thin also may be correlated with at the age.The feature lost weight occurred during illness of becoming thin can be the loss of full weight, or the loss of organ weight is as the loss of the bone caused due to the reduction of tissue protein or muscle mass.
In one embodiment, " wasting (muscle wasting) " used herein or " wasting (muscular wasting) " are used interchangeably, and refer to that the progressive loss of muscle mass and/or muscle comprise skeleton or voluntary muscle, the cardiac muscle of control heart and the gradual unable of unstriated muscle of controls movement and degenerates.In one embodiment, described wasting illness or disease are that chronic muscular is become thin illness or disease." chronic muscular marasmus " is defined as chronic (namely continuing in the long-time) progressive loss of muscle mass herein and/or muscle chronic progressive is unable and degenerate.
The feature of the loss of muscle mass occurred during muscle wasting disorder can be muscle protein breakdown through Protein catabolism or degraded.The reason that Protein catabolism occurs is proteolytic degradation speed high unusually, protein synthesis rate low unusually or the combination of the two.No matter Protein catabolism, be caused by high protein degree of degradation or caused by low albumen resultant velocity, all cause muscle mass to reduce brownization and muscle wasting disorder.Term " katabolism " has implication as known in the art, particularly refers to the energy combustion type of thanking.
The result that muscle wasting disorder can be used as pathology, disease, slight illness or illness occurs.In one embodiment, described pathology, slight illness, disease or illness are chronic.In another embodiment, described pathology, slight illness, disease or illness are genetic.In another embodiment, described pathology, slight illness, disease or illness are neuropathic.In another embodiment, described pathology, slight illness, disease or illness are infective.As described herein, the pathology that compound of the present invention and composition give, disease, the patient's condition or illness are the illnesss directly or indirectly producing muscle mass consumption (namely losing), i.e. muscle wasting disorder.
In one embodiment, in individuality, muscle wasting disorder is that individuality suffers from muscular dystrophy; Myatrophy; The chain ridge bulbar muscular atrophy (SBMA) of X; Emaciation; Malnutritive; Tuberculosis; Leprosy; Diabetes; Ephrosis; Chronic obstructive pulmonary disease (COPD); Cancer; End stage Renal failure; Sarcopenia; Pulmonary emphysema; Osteomalacia; Or myocardiac result.
In another embodiment, described muscle wasting disorder is because enterovirus, Epstein-Barr virus, zoster, HIV, trypanosome, influenza, Coxsackie virus, Rickettsiae, Trichinella spiralis, schistosomicide, mycobacterial infections cause.
Muscular dystrophy is heredopathia, it is characterized in that skeletal muscle or the gradual unable and degeneration of voluntary muscle of controls movement.Cardiac muscle and some other non-voluntary muscles are also got involved in the muscular dystrophy of some types.The main Types of muscular dystrophy (MD) is: Duchenne muscular dystrophy, myotonia atrophica, Duchenne muscular dystrophy, Becker muscular dystrophy, limb girdle type malnutrition, facio scapulo humeral type muscu lar dystrophy, congenital muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy and Emery-Dreifuss muscular dystrophy.
Muscular dystrophy may affect the crowd of institute's has age.Although some types start baby or Childhood become obvious, other type is until the middle age or later just obvious.Du Xing Shi MD is modal type, particularly affects children.Myotonia atrophica is that these diseases are modal in adult.
The feature of myatrophy (MA) is wasting or reduces and muscle mass minimizing.Such as, after poliomyelitis, MA is the muscle wasting disorder occurred as the part of post poliomyelitis syndrome (PPS).Described atrophy comprises unable, muscle fatigue and pain.
The MA of another kind of type is the chain ridge bulbar muscular atrophy of X (SBMA-is sick also referred to as Kennedy).This disease is caused by the defect of the androgen receptor gene on X chromosome, only affects the male sex, and at adult onset.Because the main cause of disease is androgen receptor sudden change, so androgen replacement is not current therapeutic strategy.More existing researchs, wherein give exogenous testosterone propionate to improve androgen levels, expect overcome androgen insensitivity and may provide anabolic action at present.The application that the testosterone of physiological levels supplements will have limitation and other potential severe complication.
Emaciation be caused by disease or as disease side effect weak and lose weight.Cardiac cachexia, namely the myoprotein of cardiac muscle and skeletal muscle is become thin, and is a feature of congestive heart failure.Cancer cachexia is the syndrome occurred in the patient suffering from solid tumor and hematologic malignancies, and it shows as and loses weight and a large amount of consumption of fatty tissue and cutability.
Emaciation also sees acquired immune deficiency syndrome (AIDS) (AIDS), and the myopathy that HIV (human immunodeficiency virus) (HIV) is relevant and/or myasthenia/become thin are the relatively common clinical manifestations of AIDS.Suffer from the myopathy or myasthenia that HIV is correlated with or the Individual Experience of becoming thin is lost weight significantly, general or centrality myasthenia, tenderness or myatrophy.
Sarcopenia is a kind of wasting diseases tormenting Senile Patients with Chronic Disease, it is characterized in that the minimizing of muscle mass and the forfeiture of function.And the increase of lean mass is relevant to the reduction of the M & M of some muscle wasting disorder.In addition, other environment is relevant with muscle wasting disorder with condition, and can cause muscle wasting disorder.Such as, research shows have paravertebral muscles to become thin in the several cases of chronic lower back pain.
Wasting is also relevant with advanced age.Think general in old-age group unablely to be caused by wasting.Along with body ages, skeletal muscle is increased by the ratio that fibrous tissue replaces.Consequently muscle strength, performance and endurance obviously decline.
The long-term inpatients caused due to ailing or damage or the useless sexual function such as occurred when limbs are fixed are degenerated and also can be caused muscle wasting disorder.Research shows to suffer from the long-term inpatients patient of damage, chronic pain, burn, wound or cancer has lasting Unilateral intramuscular to become thin, the reduction of result lean mass.
Damage or the infringement of central nervous system (CNS) are also relevant with muscle wasting disorder.Damage or the infringement of CNS such as can be caused by disease, wound or chemical substance.Example is central nervous system injury or infringement, peripheral nerve injury or infringement and Spinal injury or infringement.
In another embodiment, wasting is crapulent result, available represent embodiment of the present invention compound of the present invention and composition treat.
In one embodiment, the invention provides SARM compound for preventing the application of individual muscle wasting disorder.In another embodiment, described SARM compound is the compound of formula (I), (II), (III) or (IV).In another embodiment, described SARM compound is formula (I), (II), the compound of (III) or (IV) or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination.In another embodiment, administration comprises the pharmaceutical composition given containing described SARM and/or its prodrug, analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicine, hydrate, N-oxide compound or its arbitrary combination and pharmaceutically acceptable carrier.Thus, the muscle wasting disorder that prevention is individual.
In one embodiment, the invention provides the application that SARM compound is used for the treatment of the muscle wasting disorder relevant with chronic disease.In another embodiment, described SARM compound is the compound of formula (I), (II), (III) or (IV).In another embodiment, described SARM compound is formula (I), (II), the compound of (III) or (IV) or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination, or containing its composition.In another embodiment, the application of described SARM compound orally gives described individuality.
In one embodiment, the invention provides SARM compound for preventing the application of individual muscle wasting disorder.In another embodiment, individual muscle wasting disorder is suppressed.In another embodiment, individual muscle wasting disorder is suppressed.In another embodiment, the incidence of individual muscle wasting disorder is reduced.In another embodiment, described SARM compound is the compound of formula (I), (II), (III) or (IV).In another embodiment, described SARM compound is formula (I), (II), the compound of (III) or (IV) or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination, or containing its composition.
In another embodiment, the invention provides SARM compound of the present invention or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination, or the composition containing it is used for the treatment of, prevents, suppresses, suppresses the application of the incidence of individual muscle wasting disorder or the individual muscle wasting disorder of reduction.
In another embodiment, the invention provides SARM compound of the present invention or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination, or the composition containing it is increasing the application in individual muscle behavior expression, muscle size, muscular strength or its arbitrary combination.
In another embodiment, SARM compound of the present invention and composition are for promoting or accelerating the recovery after operation technique.
In one embodiment, the invention provides the application of SARM compound for reducing individual Fat distribution.In another embodiment, described SARM compound is the compound of formula (I), (II), (III) or (IV).In another embodiment, described SARM compound is formula (I), (II), the compound of (III) or (IV) or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination, or containing its composition.
In another embodiment, the invention provides SARM compound of the present invention, such as there is formula (I), (II), the compound of structure of (III) or (IV) or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination, or containing its application of composition in the individual obesity relevant with metabolism syndrome for the treatment of or diabetes.
In one embodiment, described individuality suffers from hormone imbalances, disorder or disease.In another embodiment, described individuality is that menopause is individual.
In one embodiment, the invention provides SARM compound for increasing the thin heavy application of individuality.In another embodiment, described SARM compound is the compound of formula (I), (II), (III) or (IV).In another embodiment, described SARM compound is formula (I), (II), the compound of (III) or (IV) or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination.Thus, increase individual thin heavy.
In another embodiment, described individuality suffers from hormone imbalances, disorder or disease.In another embodiment, described individuality is that menopause is individual.
Fig. 3-7 shows compound III to be excito-anabolic and to have minimum short male active, and thus these compounds can be used for treating that wherein pass by male sex hormone be the patient group avoided.Proved no matter testosterone whether in the presence of the equal stimulated muscle growth of compound III, play antiproliferative effect to prostate gland, thus in one embodiment, SARM of the present invention recovers the muscle mass of the forfeiture of Sarcopenia or cachectic patients simultaneously.
In one embodiment, SARM of the present invention is through being administered to individual intravenous administration by the described pharmaceutical composition of liquid form.In another embodiment, SARM of the present invention is through being administered to individual intraarterial delivery by the described pharmaceutical composition of liquid form.In another embodiment, SARM of the present invention is through being administered to individual intramuscular administration by the described pharmaceutical composition of liquid form.In another embodiment, SARM of the present invention is through implanting individual subcutaneous administration by the piller containing described pharmaceutical composition.In another embodiment, SARM of the present invention is by giving individual oral administration by the described pharmaceutical composition of liquid or solid form.In another embodiment, SARM of the present invention is through being applied to individual skin surface topical by described pharmaceutical composition.
In one embodiment, the invention provides safety and the muscle loss being effectively used for the treatment of, preventing, suppressing, suppressing or reducing because muscle wasting disorder causes and/or the catabolic method of mytolin.In another embodiment, the present invention is used for the treatment of the individuality of suffering from muscle wasting disorder or in another embodiment, is used for the treatment of the individuality suffering from bone-related disorder.In another embodiment, described individuality is mammalian subject.
In one embodiment, the present invention relates to prevention, compacting, suppress individual fat or reduce the method for individual fat incidence, it comprises effectively preventing, suppressing, suppress individual fat or reduce the SARM of the present invention (SARM) of amount of individual fat incidence and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, crystal or its arbitrary combination give described individuality.
In one embodiment, SARM compound of the present invention changes individual leptin (leptin) level.In another embodiment, SARM compound reduces leptin level.In another embodiment, SARM compound of the present invention increases individual leptin level.The appetite of known leptin on obesity mice has impact, and make weight saving, therefore it is relevant with obesity.
In one embodiment, SARM of the present invention affects the cyclical level of leptin, or in one embodiment, what affect leptin organizes level.In one embodiment, term " leptin level " refers to the serum level of leptin.As contemplated herein, all to leptin, there is effect in SARM Compound ira vitro of the present invention and body.Leptin level can be measured by method known to those skilled in the art, such as, measured by the ELISA kit of commercially available acquisition.In addition, leptin level is determined through external test or in vivoassay by any method well known by persons skilled in the art.
Because leptin participates in appetite control, weight saving, food intake and energy expenditure, therefore regulating and/or controlling leptin level treating, preventing, suppress to suffer from the obesity of fat individuality or reduction to suffer from the incidence of fat individuality obesity is useful methods for the treatment of.Regulate the level of leptin that the decline of individual appetite, food intake minimizing and energy expenditure can be caused to increase, thus may contribute to control and treat fat.
In one embodiment, term " obesity " is defined as the restriction increasing above bone and somagenic need of body weight, and result is fat excessive buildup in vivo.
In one embodiment, term " fat relevant metabolic disorder " refer to that obesity causes, as the result of obesity, obesity aggravates or be secondary to fat illness.The limiting examples of described illness is osteoarthritis, type ii diabetes, hypertension, apoplexy and heart trouble.
In another embodiment, term " osteoarthritis " refers to the degenerative joint disease of the non-inflammation mainly occurred in the elderly, it is characterized in that the sex change of joint cartilage, hyperostosis and synovial membrane edge and synovial membrane change.In another embodiment, it is attended by pain and stiff, particularly after long-time activity.
In one embodiment, term " diabetes " refers to that the relative or absolute shortage of Regular Insulin causes carbohydrate metabolism uncontrolled.Most patients can classify as insulin-dependent diabetes (IDDM or type i diabetes) or non-insulin-dependent diabetes mellitus (NIDDM) (NIDDM or type ii diabetes) clinically.
In other embodiments, term " elevation of blood pressure " or " hypertension " refer to the hypertension repeatedly at more than 140/90mmHg.Chronic hypertension can cause that optical fundus blood vessel changes, cardiac muscle thickens, renal failure and cerebral lesion.
In other embodiments, term " apoplexy " refers to the infringement of the brain nervous cell that the blood supply insufficiency usually caused because of angiorrhexis or blood clot causes.In other embodiments, term " heart trouble " refers to heart normal function and active dysfunction, comprises cardiac failure.
In addition, proved that male sex hormone participation interstitial pluripotent cell is orientated myogenous cells system and stops recently and be divided into adipose cell lines (Singh etc., Endocrinology, 2003, Jul 24).Therefore, SARM compound can be used for blocking steatogenesis as described herein and/or changing in the method for differentiation of stem cells.
In another embodiment, the method that the present invention relates to promotion, increase or help whose body weight to alleviate, it comprises the step SARM of the present invention (SARM) of the amount effectively promoting, increase or help whose body weight to alleviate and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, crystal or its arbitrary combination being given described individuality.
In another embodiment, the present invention relates to reduction, suppress, suppress or reduce the method for individual appetite, it comprises the step that the SARM of the present invention (SARM) of the amount by effectively reducing, suppressing, suppress or reduce individual appetite and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, crystal or its arbitrary combination give described individuality.
In another embodiment, the present invention relates to the method changing individual body composition, it comprises the step that the SARM of the present invention (SARM) of the amount by effectively changing individual body composition and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, crystal or its arbitrary combination give described individuality.In one embodiment, change body composition and comprise the individual lean mass of change, fat free body weight or their combination.
In another embodiment, the present invention relates to the method changing individual lean mass or fat free body weight, it comprises the step that the SARM of the present invention (SARM) of the amount by effectively changing individual lean mass or fat free body weight and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, crystal or its arbitrary combination give described individuality.
In another embodiment, the present invention relates to individual adipose conversion is the method for lean meat, and it comprises effective step by individual adipose conversion being the SARM of the present invention (SARM) of the amount of lean meat and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, crystal or its arbitrary combination and giving described individuality.
In another embodiment, the present invention relates to the method for the individual fat relevant metabolic disorder for the treatment of, it comprises the step that the SARM of the present invention (SARM) of the amount by effectively treating individual fat relevant metabolic disorder and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, crystal or its arbitrary combination give described individuality.
In another embodiment, the present invention relates to the method for the relevant metabolic disorder of prevention, compacting, suppression or minimizing individuality obesity, it comprises the step SARM of the present invention (SARM) of the amount of the metabolic disorder effectively preventing, suppress, suppress or reduce individuality obesity to be correlated with and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, crystal or its arbitrary combination being given described individuality.
In one embodiment, the metabolic disorder that described obesity is relevant is hypertension.In another embodiment, described illness is osteoarthritis.In another embodiment, described illness is type ii diabetes.In another embodiment, described illness is elevation of blood pressure.In another embodiment, described illness is apoplexy.In another embodiment, described illness is heart trouble.
In another embodiment, the present invention relates to reduction, suppress, suppress or reduce individual lipogenetic method, it comprises the step SARM of the present invention (SARM) and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, crystal or its arbitrary combination that effectively reduce, suppress, suppress or reduce individual lipogenetic amount being given described individuality.
In another embodiment, the present invention relates to the method changing individual differentiation of stem cells, it comprises the step that the SARM of the present invention (SARM) of the amount by effectively changing individual differentiation of stem cells and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, crystal or its arbitrary combination give described individuality.
In another embodiment, the present invention relates to the method changing individual leptin level, it comprises the step that the SARM of the present invention (SARM) of the amount by effectively changing individual leptin level and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, crystal or its arbitrary combination give described individuality.
In another embodiment, the present invention relates to reduction, suppress, suppress or reduce the method for individual leptin level, it comprises the step that the SARM of the present invention (SARM) of the amount by effectively reducing, suppressing, suppress or reduce individual leptin level and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, crystal or its arbitrary combination give described individuality.
In one embodiment, for following SARM be formula (I), (II), the representative of (III) or (IV) structure compound: a) treat, prevention, compacting, suppress or reduce fat; B) promote, increase or help to lose weight; C) reduce, suppress, suppress or reduce appetite; D) body composition is changed; E) lean mass or fat free body weight is changed; F) be lean meat by adipose conversion; G) treat, prevent, suppress, suppress or reduce the metabolic disorder that individual obesity is correlated with, such as hypertension, osteoarthritis, type ii diabetes, elevation of blood pressure, apoplexy or heart trouble; H) reduce, suppress, suppress or reduce individual steatogenesis; I) differentiation of stem cells is changed; And/or j) change leptin level.
In one embodiment, find that SARM compound of the present invention is at treatment or prevention diabetes development, or useful in treatment diabetic symptom.In another embodiment, SARM compound of the present invention is used for the treatment of the relevant common disease of diabetes.These illnesss comprise: hypertension, cerebrovascular disease, atherosclerosis coronary artery disease, macular degeneration, diabetic retinopathy (illness in eye) and blind, cataract-systemic inflammatory (being characterised in that Markers of inflammation such as erythrosedimentation speed or C reactive protein raise), inborn defect, the diabetes that gestation is relevant, preeclampsia and gestational hypertension, ephrosis (renal insufficiency, renal failure etc.), neuropathy (diabetic neuropathy), surface and Systemic fungal infections, congestive heart failure, gout/hyperuricemia, fat, hypertriglyceridemia, hypercholesterolemia, the tetter that Fatty Liver Disease (non-alcoholic fatty liver disease or NASH) and diabetes are correlated with is as necrobiosis lipoidica diabeticorum (NLD), diabeticorum (diabetic blister is sick), eruptive xanthomatosis, refer to sclerosis, dispersivity annular granuloma and acanthosis nigricans.
In one embodiment, the invention provides for following method: a) treat, prevent, suppress, suppress atherosclerosis; B) hepatic injury treat, prevent, suppress, suppressing because fatty deposits causes, it comprises will effectively treat, prevent or suppress atherosclerosis and the SARM of the present invention (SARM) of the amount of hepatic injury that causes due to fatty deposits and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, crystal or its arbitrary combination, or the composition containing it gives individual step.
In one embodiment, SARM compound of the present invention is used for: a) treat, prevent, suppress, suppress or reduce atherosclerosis; B) hepatic injury treat, prevent, suppress, suppressing because fatty deposits causes.
In one embodiment, atherosclerosis refer to can from infringement artery innermost layer chronic, complex disease.In another embodiment, the reason damaging arterial wall can comprise a) Blood Cholesterol level and raise; B) hypertension; C) smoke of tobacco; D) diabetes.In another embodiment, although smoke of tobacco may make atherosclerosis more worsen and accelerate that it grows in coronary artery, Aorta and leg arteries to be true, this illness is medicable in smoker.Similarly, in another embodiment, method of the present invention can be used for treating the individuality with vascular disease family medical history of making up one's mind the morning increasing Atherosclerosis Risk.
In one embodiment, the hepatic injury caused due to fatty deposits refers to increasing of in the liver cell forming fatty liver fat, wherein said fatty liver may with the inflammation-related of liver or the inflammation causing liver.This can cause scar and the sclerosis of liver.When scar becomes extensive, be called cirrhosis.In another embodiment, fat accumulation, in liver, becomes fat.In another embodiment, fatty liver is also relevant with excessive use alcohol to diabetes, hypertriglyceridemia.In another embodiment, fatty liver can with some disease as pulmonary tuberculosis and excessive vitamin A in malnutritive, fat intestines by-pass operation, body or use some drugs occur as valproic acid (trade(brand)name: Depakene/Depakote) and reflunomide (cortisone, prednisone).Sometimes fatty liver occurs as pregnancy complications.
In one embodiment, be used for the treatment of in individual method, described individuality is people, and in another embodiment, described individuality is the male sex, or in another embodiment, described individuality is women.
In another embodiment, the invention provides SARM of the present invention or the application of composition in promotion or the spermatogenesis of compacting male individual containing it.SARM more of the present invention show short male active in addition, therefore stimulate spermatogenesis.In another embodiment, SARM of the present invention shows antagonistic activity in the sexual gland of individuality, therefore can suppress spermatogenesis.In one embodiment, therefore described SARM can be used as contraceptive bian.
Should understand, any application of SARM of the present invention, the application comprised particularly in the application about the disease relevant with muscle, fat, heart, liver, sexual gland or osseous tissue or illness is also a part of the present invention, wherein SARM compound of the present invention or containing its composition give the course of disease advantageously changing these diseases or illness.
There is provided following embodiment more fully to illustrate the preferred embodiments of the invention.But, never they should be interpreted as and limit wide protection domain of the present invention.
embodiment
embodiment 1:
sARM (SARM) compound III is scleroblast to ancestor cell differentiates and breaks the effect of osteocyte
materials and methods
Pharmaceutical chemicals
Compound III, THT and PTH are prepared with the concentration of 1nM-1 μM.
Animal
Four monthly age female rats euthanasia, by animal distal femoral resection.Any muscle on removing femur and reticular tissue, and in storing until cell cultures on ice in the minimum essential medium (MEM) containing penicillin, Streptomycin sulphate and amphotericin B.
Medullary microeirculation
All cell culture materials are all purchased from Invitrogen (Carlsbad, CA).First femur is cleaned in 70% ethanol, and wash three times with penicillin and each 5ml of Streptomycin sulphate.All fractureed at femur two ends, medullary cell 15ml rinses in 50ml tapered tube containing the MEM of penicillin, Streptomycin sulphate and amphotericin B, and stores on ice.Same step is carried out to all femurs.Medullary cell is mixed, and in clinical centrifuge with 1000rpm centrifugal 5 minutes.Cell is resuspended in not containing phenol red and in the MEM of the serum of supplementary 10% active carbon desorption, penicillin, Streptomycin sulphate and amphotericin B.Cell is passed through 22g pin with grinding, counted under microscope, with every hole 1,500,000 cell be seeded in 6 orifice plates not containing phenol red and in the MEM of the serum of supplementary 15% active carbon desorption, penicillin, Streptomycin sulphate, 300ng/ml amphotericin B, 0.28mM xitix and 10mM β-Phosphoric acid glycerol esters, to break up to inoblast/scleroblast system, and with every hole 2,500,000 cell be seeded in 24 orifice plates not containing phenol red and in the MEM of the amphotericin B of the serum of supplementary 10% active carbon desorption, penicillin, Streptomycin sulphate and 300ng/ml, to break up to osteoclast system.Replaced medium on the 2nd, and use described HORMONE TREATMENT.Osteoclast culture carries out inducing osteoclast to generate under 50ng RANK part and 10ng GM-CSF exist.For Osteoclast culture, the complete replaced medium every three days.For osteoblasts cultivation, changed half substratum every three days to leave the somatomedin of emiocytosis.
Cell dyeing
When 12 end of day, cell is fixed in 10% buffered formalin by fibroblast cell cultures, and cell is fixed in 4% formaldehyde by Osteoclast culture thing.Inoblast is used for alkaline phosphatase activities dyeing, uses spectrophotometer to measure O.D. as mentioned previously under 405nm.Osteoclast is used for Tartrate resistant acid phosphatase activity (TRAP) dyeing, and counting has the cell of 2 or more cores under the microscope, and maps as mentioned previously.
result
sARM is the strong inductor that medullary cell breaks up to scleroblast and osteoclast system
Male sex hormone has anabolic action to bone, lacks male sex hormone in some cases and clearly illustrated that the benefit of male sex hormone as bone protection hormone in the Androgen deprivation therapy of such as prostate cancer and the elderly.But, the androgenic use of dystopy due to its side effect and due to androgen conversion be that estrogenic risk is restricted.
In order to determine whether SARM can have therapeutic action and avoid above-mentioned side effect; there is with regard to SARM (SARM) ability and less side effect aspect (seen by female hormone) of bone provide protection, various SARM is evaluated.Make rat primary medullary cell to the ability aspect of scleroblast and the differentiation of osteoclast system with regard to dihydrotestosterone (DHT) and parathyroid hormone (PTH) and SARM compound III, the effect of dihydrotestosterone (DHT) and parathyroid hormone (PTH) and SARM compound III are compared (Fig. 1 and 2).Under the above hormone presence or absence, rat bone marrow cell is cultivated 12 in the medium, and evaluate to scleroblast and osteoclast system differentiation aspect with regard to them.
DHT and compound III all increase the differentiation of primary bone marrow cells to scleroblast system, as shown in alkaline phosphatase (ALP) activity measurement of cell (Fig. 1).Under 1 μM of concentration, the ALP that DHT and SARM induction phase is worked as is active, and under low concentration 100nM and 10nM, compound III display has larger induction than DHT, PTH, another bone anabolic hormone only induces ALP to dye at higher concentrations and not under low concentration.
Fig. 2 shows when cell is cultivated under RANK part and GM-CSF exist, the obvious increase of the quantity of the positive multinucleated osteoclast of TRAP.The positive multinucleated osteoclast propagation of the TRAP of RANK part and GM-CSF induction is significantly suppressed with the cell of DHT or SARM process.PTH suppresses induction at higher concentrations, but under low concentration, PTH but adds the quantity of TRAP positive osteoclasts.Under the dosage of all evaluations, estradiol all suppresses osteoclast to generate.
embodiment 2:
sARM separately and the bone effect of combining with antiresorptive agent Alendronate
materials and methods
60 female, unpregnancies, complete 23 week age Sprague-Dawley rat obtain from Charles RiverLaboratories (Wilmington, MA).2-3 animal raised by every cage, and adapt to 12-h illumination/dark cycle.Freely obtain food (7012C LM-485 mouse/rat sterilization diet, HarlanTeklad, Madison, WI) and water.The Institutional Animal Care and Use Committee of the animal protocol Shu Huo Tennessee state university of the research examines and approval.
Sham-operation or ovariectomy were carried out on 0th.This research is made up of following six treatment group: (1) complete+and carrier, (2) complete+compound III, (3) OVX+ carrier, (4) OVX+ compound III, (5) OVX+ Alendronate, (6) OVX+ Alendronate+compound III.DMSO:PEG300 (10:90) vehicle group started every Nikkei tube feed on 1st and gives dosage (200L).Execution animal on the 45th of this research.Take out femur, remove soft tissue, and store at-20 DEG C until analyze in SS saline soaked gauze.9 animal deads are had during studying.The complication that these death cause owing to ovariectomy and the technology mistake (being namely delivered in lung to drug solns) in oral administration.Dosage group is listed in Table 1.
Table 1, treatment group
Fl is sent to SkeleTech Inc. (Bothell, WA) to analyze for biomechanical strength (three-point bending method) and pQCT.Stratec XCT RM and related software (Stratec MedizintechnikGmbH, Pforzheim, Germany.Software version 5.40C) are analyzed for pQCT.All analyze in femur stage casing and remote area.Middle piecewise analysis is carried out in the region at 50% place of femur length.The region at 20% place of the femur length that far-end analysis starts at distally end is carried out.The thin slice perpendicular to the 0.5mm of femur major axis is used to be used for analyzing.Total bone mineral content, total surface of bone long-pending, total bone mineral density, cortex bone mineral content, cortex bone area, cortex bone mineral density, cortical thickness, periosteum girth (circumferentia) and perimyelis girth measure in femur stage casing.Total bone mineral content, total surface of bone long-pending, total bone mineral density, trabecular bone mineral content, trabecular bone area and trabecular bone mineral density is measured in distal femur.After pQCT analyzes, femoral strength is measured by three-point bend test.The radius vector (APD) (unit: mm) of femur stage casing mid point is measured by electronic caliper.On pillar below three-point bending device femur being placed in Instron Mechanical Testing Machine (it is 5500 that Instron 4465 has renovated) (Canton, MA), to make before femur down.Length (L) between underlying brace is set as 14mm.The device of top load is made to aim at the center in femur stage casing.Use constant bit-rate 6mm/min until femur fractures.Overall loading (F directly measured by mechanical test instrument u) (unit: N), stiffness (S) (unit: N/mm) and absorption can (W) (units: mJ).Axial area moment of inertia (I) (unit: mm 4) calculated by the software during femur stage casing pQCT analyzes.Stress (σ) (unit: N/mm 2), Young's modulus (E) (unit: Mpa) and intensity (T) (unit: mJ/m 3) calculated by following formula: stress: σ=(F u* L* (a/2))/(4*L); Young's modulus: E=S*L 3/ (48*I); And intensity: T=3*W* (APD/2) 2/ (L*I).
Statistical analysis passes through Student ' s T inspection and carries out.Think that P-value has statistically-significant difference when being less than 0.05.
Result:
Femur overall loading is measured by the 3-point bending method of femur.Result display in figure 3.Difference is not observed between complete vector (210N) control group and OVX carrier (212N) control group.We observe compound III treatment group and compare with OVX group with close set respectively and have the trend that overall loading increases to 224 and 233 newton.Alendronate (213N) does not have difference with Alendronate+compound III (207N) group compared with control group.
The trabecular bone mineral density of distal femoral is analyzed by pQCT.Result display in the diagram.We are significant trabecular bone loss after observing OVX.In complete vector control group and OVX vehicle Control group, trabecular bone density is down to 215mg/cm from 379 respectively 3.In the intact animal with compound III process, we observe trabecular bone density slightly increases and reaches 398mg/cm 3.With in the OVX animal of compound III process, we observe and significantly increase to 406mg/cm relative to OVX vehicle Control group 3.The trabecular bone density of clinic effect of alendronate Ficus caricaL increases to 480mg/cm 3.The combination therapy display of Alendronate and compound III is added effectiveness, makes trabecular bone density increase to 552mg/cm 3.
embodiment 3:
short male active A MP.AMp.Amp anabolic activity in complete and ORX rat
materials and methods
The male Spargue-Dawley rat of heavily about 200g is purchased from Harlan Bioproducts forScience (Indianapolis, IN).Animal is kept 12 h light/dark cycle, and freely can obtain food (7012C LM-485 mouse/rat sterilization diet, Harlan Teklad, Madison, WI) and water.The Institutional Animal Care and UseCommittee of animal protocol Shu Huo Tennessee state university examines and approval.The anabolism of assessing compound III in intact animal and short male activity, also evaluate the dose response in acute testicular surgical blanking (ORX) animal in addition.Also been evaluated the regeneration of compound III in chronic (9 days) ORX rat.
Described compound is weighed and is dissolved in 10% DMSO (Fisher) using PEG 300 (Acros Organics, NJ) to dilute, for the preparation of suitable dose concentration.2-3 animal is raised in each cage.Become 7 groups by complete with the random assignment of ORX animal, often group is made up of 4-5 animal.Control group (complete and ORX) give carrier every day.I through tube feed by compound III with dosage 0.01,0.03,0.1,0.3,0.75 with give complete and ORX group 1mg/ day.
Neuter (first day in this research) is divided at random 0.01,0.03,0.1,0.3,0.75 and 1mg/ per daily dose group (4-5 animal/group), for dose response evaluation.After ORX 9 days start administration, through tube feed daily 14 days.After dosage regimens on the 14th, Animal Anesthesia (ketamine/dimelazine (xyalzine), 87:13mg/kg) is put to death, and record body weight.In addition, take out prostate gland siphonal lobe, seminal vesicle and musculus levator ani, weigh separately, carry out stdn according to body weight, represent with the per-cent of Intact control group.Student ' s T is used to check more independent dosage group and Intact control group.P value <0.05 prior definitions is remarkable.As short male active measuring, row gland siphonal lobe and seminal vesicle weights are evaluated, and levator ani muscle weight is measured as evaluation is anabolic.Blood is collected from aorta abdominalis, centrifugal, before measurement hormone serum level, serum is frozen at-80 DEG C.Serum lutropin (LH) and follicle stimulating hormone (FSH) concentration are measured by Fu Jiliya university Center for Research in Reproduction Ligand Assayand Analysis Core (NICHD (SCCPRR) Grant U54-HD28934).
result:
After giving dosage 0.01,0.03,0.1,0.3,0.75 and 1mg/ day, the weight of prostate after compound III process is 111% ± 21%, 88% ± 15%, 77% ± 17%, 71% ± 16%, 71% ± 10% and 87% ± 13% (Fig. 5) of Intact control group respectively.Similarly, after giving dosage 0.01,0.03,0.1,0.3,0.75 and 1mg/ day, seminal vesicle weights reduces to 94% ± 9%, 77% ± 11%, 80% ± 9%, 73% ± 12%, 77% ± 10% and 88% ± 14% of Intact control group respectively.But in all dosage groups when compared with Intact control, the levator ani muscle weight observing sham-operation animal significantly increases.Corresponding to 0.01,0.03,0.1,0.3,0.75 and 1mg/ per daily dose group, levator ani muscle weight is 120% ± 12%, 116% ± 7%, 128% ± 7%, 134% ± 7%, 125% ± 9% and 146% ± 17% of Intact control respectively.Result provides with chart in Figure 5.
After male castration, compound III part keeps weight of prostate.In the ORX contrast of vehicle treated, weight of prostate is down to 5% ± 1% of Intact control.Dosage be 0.01,0.03,0.1,0.3,0.75 and 1.0mg/ day time, compound III keeps weight of prostate to be 8% ± 2%, 20% ± 5%, 51% ± 19%, 56% ± 9%, 80% ± 28% and 74% ± 12.5% of Intact control respectively.In castrating contrast, seminal vesicle weights is down to 13% ± 2% of Intact control group.In ORX animal, compound III part keeps seminal vesicle weights.After giving 0.01,0.03,0.1,0.3,0.75 and 1.0mg/ per daily dose, the seminal vesicle weights of the animal of drug treating is respectively 12% ± 4%, 17% ± 5%, 35% ± 10%, 61% ± 15%, 70% ± 14% and 80% ± 6% of Intact control.In ORX contrast, levator ani muscle weight is down to 55% ± 7% of Intact control group.In the musculus levator ani of the animal of compound III process, we observe anabolic action.Compound III keeps levator ani muscle weight completely when dosage >0.1mg/ day.Compared with observing with in Intact control, dosage >0.1mg/ day causes levator ani muscle weight significantly to increase.For 0.01,0.03,0.1,0.3,0.75 and 1.0mg/ per daily dose group, with the percentages of Intact control group, levator ani muscle weight is 59% ± 6%, 85% ± 9%, 112% ± 10%, 122% ± 16%, 127% ± 12% and 129.66% ± 2%.Result provides with chart in figure 6.At the E of each tissue maxand ED 50value is passed through in nonlinear regression analysis determine, and to provide in the figure 7.The E of prostate gland, seminal vesicle and musculus levator ani maxvalue is 83% ± 25%, 85% ± 11% and 131% ± 2% respectively.The ED of prostate gland, seminal vesicle and musculus levator ani 500.09 ± 0.07,0.17 ± 0.05 and 0.02 ± 0.01mg/ day respectively.
serum hormone is analyzed
Serum Lh and the FSH data of animal provide in Table 1.In complete and neuter, LH all reduces with dosage-dependent manner.After giving dosage >0.1mg/ day, LH level is lower than quantitative limit (0.07mg/ day).In ORX animal, 0.1mg/ per daily dose makes LH level get back to level seen in Intact control group.Similar effect is also observed for FSH.In intact animal, 0.75 and 1mg/ per daily dose observe FSH level and significantly reduce.In ORX animal, observe FSH levels dosages dependency and reduce.In ORX animal, the FSH level that makes dosage >0.1mg/ day of compound III gets back to Intact control level.
The serum Lh of table 1.Arm1 and Arm2 animal and FSH level. ap<0.05vs. Intact control. bp<0.05vs.ORX contrasts.
postpone the short male active A MP.AMp.Amp anabolic activity after administration
In ORX animal, compound III part recovers prostate gland and seminal vesicle weights.For 0.01,0.03,0.1,0.3,0.75 and 1.0mg/ per daily dose group, prostate gland returns to 9% ± 3%, 11% ± 3%, 23% ± 5%, 50% ± 13%, 62% ± 12% and 71% ± 5% of Intact control respectively, and seminal vesicle regains one's integrity contrast 7% ± 1%, 9% ± 1%, 23% ± 8%, 49% ± 5%, 67% ± 12% and 67% ± 11%.Compound III, when dosage >0.1mg/ day, recovers levator ani muscle weight completely.Corresponding to dosage 0.01,0.03,0.1,0.3,0.75 and 1.0mg/ day, levator ani muscle weight returns to 56% ± 7%, 82% ± 9%, 103% ± 11%, 113% ± 11%, 121% ± 7% and 120% ± 7% respectively.Result provides with chart in fig. 8.The E of each tissue maxand ED 50value is passed through in nonlinear regression analysis determine, and to provide in fig .9.The E of prostate gland, seminal vesicle and musculus levator ani maxvalue is 75% ± 8%, 73% ± 3% and 126% ± 4% respectively.The ED of prostate gland, seminal vesicle and musculus levator ani 500.22 ± 0.05,0.21 ± 0.02 and 0.013 ± 0.01mg/ day respectively.
embodiment 4:
the Pharmacokinetic Characteristics of new oral anabolism SARM compound III:
analysis first in healthy male volunteers
materials and methods
With randomized, double-blind research and design, with each dosage level (9 activity, 3 placebos), administration is carried out to maximum one group of 12 healthy male volunteers.Recruit 8 groups (age 18-45 years), often group receives once single oral dosage, and described dosage is corresponding to 1 in the solution, 3,10,30 and 100mg compound III (or isopyknic PEG 300 placebo) or 3 or 30mg compound III in test capsule.Micronization (the namely particle diameter reduces) impact on the pharmacokinetics of compound III is have studied with the form of 30mg solid oral dosage form.Sample for female medicine Pharmacokinetic Evaluation is collected upon administration and is reached 72 hours.
result
Dosage be 1,3,10,30 and the compound III in PEG300 based sols of 100mg fast from gastrointestinal absorption.All dosage waters on average cause a to the last all gageable compound III plasma concentration (Figure 10-12) of collection time point (72 hours).Contact (the C of compound III maxand AUC) increase with dosage and increase, and linear within the scope of dosage 1-100mg for solution.For the compound III in solution, obtain T in 0.8 and 2.3 little times (intermediate value=1.0 hour) max, and obtain T in 3.2 and 3.9 little times after giving solid orally ingestible max(Figure 13 and 14).For 1-100mg solution and 3mg capsule, the transformation period is eliminated at end is eventually 19 to 22 hours (intermediate value=20 hour), for 30mg micronization and non-micronization capsule, increase to 27 and 30 hours, but there is no significance (p>0.1).Oral clearance and transformation period are oppositely relevant, compare with dosage with other formulation, the long half-lift that the non-micronization capsule of 30mg showing most and minimum clearing rate.3mg non-micronization capsule and solution have equal bioavailability, but improve oral administration biaavailability (p<0.5) (Figure 12) in higher dosage (30mg) micronization.Eliminate as indicated in continuous print second peak mutually as medicine, it is possible that the enterohepatic circulation through liver and gall plays an important role in the redistributing of female medicine.
embodiment 5
the anabolism of SARM and short male activity
Material: according to the method synthesis SARM described in U.S. Patent Application Publication 2004/0014975A1.Alzet osmotic pump (2002 type) is purchased from Alza Corp. (Palo Alto, CA).
The SARM of test will comprise as follows:
With
Their activity and the expression activitiy of following compound:
Research and design: by the Sprague-Dawley rat random packet of immature heavy 90-100mg, often organize at least 5 animals.One day before starting drug treating, take out single for animal from cage, weigh and give ketamine/dimelazine (87/13mg/kg by intraperitoneal; About 1mL/kg) anesthesia.When suitable anesthesia (namely not reacting pinching toe), for the ear of animal is marked by the object confirmed.Then animal is placed on sterile pad, with povidone iodine and its belly of 70% ethanol purge and scrotum.Cut via middle line of scrotum and take out testis, aseptic suture is used for ligation testis top tissue, the then each testis of surgical removal.Close surgical wound site by aseptic stainless steel wound clips, and clean this position with povidone iodine.Allow animal revive on sterile pad (until can stand), then they are put back in cage.
After 20 hours, with ketamine/dimelazine, animal is anaesthetized again, and by the Alzet osmotic pump (2002 type) containing SARM compound through subcutaneous placement in omoplate district.Osmotic pump contains the suitable medicine (as described in Example 3) be dissolved in Liquid Macrogol (PEG 300).Within 1st, fill osmotic pump with suitable solution before implantation.Every day, monitor animal was to the acute toxic symptoms (as drowsiness, rough coat) of drug treating.
Drug treating is after 14 days, with ketamine/dimelazine anesthetized animal.By sacrificed by exsanguination animal under anaesthesia.Collect blood sample by aorta abdominalis venipuncture, and carry out whole blood cell analysis.A part of blood sample is placed in separator tube, with 12000g centrifugal 1 minute.Removing plasma layer is also frozen at-20 DEG C.Take out prostate gland siphonal lobe, seminal vesicle, musculus levator ani, liver, kidney, spleen, lung and heart, remove other tissue, weigh and be placed in the bottle containing 10% neutral buffered formalin.Preserved tissue is used for histopathological analysis.
For data analysis, the weight of all organs carries out stdn with body weight, carries out statistical significant difference analysis by single factor test ANOVA.The weight of prostate gland and seminal vesicle is as evaluating short male active index, and levator ani muscle weight is for evaluating anabolic activity.
To increase the testosterone propionate (TP) of dosage as anabolism and the short male positive controls acted on.Thus the effect of specific compound and TP can be compared.
Expect the weight of prostate gland, seminal vesicle and musculus levator ani produces because of endogenous androgens in the rat of castrating, vehicle treated cut-out and significantly reducing.Expection testosterone propionate, short external source that is male and anabolic steroid give the weight by increasing castrating rat prostate, seminal vesicle and musculus levator ani with dosage-dependent manner.To comparatively evaluate the impact of SARM on the weight of neuter prostate gland, seminal vesicle and musculus levator ani.The lower usefulness of display and intrinsic activity in the weight increasing prostate gland and seminal vesicle, and in the weight increasing musculus levator ani, show the compound of higher performance and intrinsic activity, to be considered to short male weak, but there is anabolic activity, represent and will be used for the treatment of such as prostate cancer or be used for the treatment of the compound for the treatment of side effect as relevant in Androgen deprivation therapy to prostate cancer at present.
embodiment 6
sARM is to the reduction of the level of cholesterol
materials and methods
Be divided into 5 groups (often organizing often kind of sex n=10) by 100 Spargue Dawley rats (50 male and 50 female), its representative only has carrier (PEG 300:40% [75/25 (v/v)]) four dosage groups of group and compound III.Once a day compound III is given with the dosage of 0,3,10,30 or 100mg/kg by tube feed according to their nearest body weight by animal.During studying, rat arbitrarily drinks water and Harlan Taklad Rodent Chow standard laboratory diet.Successive administration, after 28 days, by animal overnight fasting, collect blood sample, and process is to obtain serum.Automatic laboratory determination method is used to measure serum total cholesterol level.
result
92 ± 13.5 and 102 ± 13mg/L is respectively only having the male and serum cholesterol value that is female rats in vehicle group (0mg/kg).Think that these values are in the normal historical range of test laboratory.Compound III every day, oral dosage was 3mg/kg or higher time in male and female rats, all cause total cholesterol level significantly to reduce.When 3mg/kg, compared with vehicle control animals, notice that total cholesterol reduces about 30%, wherein male and be femalely respectively 63 ± 17.4 and 74 ± 14.2mg/L.Although noticing has slight larger effect in maximum dose level group (100mg/kg/ day), in general, in Spargue Dawley rat, do not observe dose-response relationship about the minimizing of total cholesterol level.This result provides in fig .15 in graphical form.
Evaluation SARM is being caused the effect in acute toxicity, test by diagnosis hematology and dock subject animal vision inspection and measure, by the compacting lutropin (LH) such as described in above embodiment 4 or follicle stimulating hormone (FSH).
Although illustrated herein and described some feature of the present invention, many amendments will be there is to those skilled in the art, substitute, change and be equal to substitute.It is therefore to be understood that appended claim is intended to contain all modifications and variations fallen in connotation of the present invention.

Claims (36)

1. SARM (SARM) compound represented by the structure of formula (III) or its pharmacologically acceptable salts or its arbitrary combination:
2. a composition, it contains the SARM compound of claim 1 and suitable carrier or thinner.
3. the composition of claim 2, it is also containing Alendronate.
4. the composition of claim 3, wherein said compound is 3 to 1 with the ratio of described Alendronate.
5. claim 1 SARM compound or containing its composition for the preparation for the treatment of the application suffered from the medicine of the individuality of bone-related disorder.
6. the application of claim 5, wherein said bone-related disorder is osteoporosis, bone resorption increases, fracture, bone are fragile or its arbitrary combination.
7. the application of claim 5, wherein bone-related disorder is osteopenia.
8. the application of claim 5, wherein bone-related disorder is that bone mineral density (BMD) reduces.
9. the application of claim 5, wherein said composition is also containing Alendronate.
10. claim 1 SARM compound or containing its composition for the preparation of increasing individual bone strength or bone amount or promoting the application in individual osteoplastic medicine.
The application of 11. claims 10, wherein said composition is also containing Alendronate.
The application of 12. claims 10, wherein said bone is cortex bone.
The application of 13. claims 10, wherein said bone is trabecular bone or spongy bone.
The application of 14. claims 10, wherein said SARM compound stimulates or is enhanced to osteocyte generation.
The application of 15. claims 10, wherein said SARM compound suppresses osteoclast proliferation.
The application of 16. claims 10, wherein said individuality suffers from Sarcopenia or emaciation.
The SARM compound of 17. claims 1 or containing its composition for the preparation of intervene or preventing osteoporosis medicine in application.
The application of 18. claims 17, wherein said osteoporosis is that hormone causes.
The SARM compound of 19. claims 1 or containing its composition for the preparation of the application intervened or in medicine that prevention of osteoporosis reduces.
The SARM compound of 20. claims 1 or containing its composition for the preparation of treat, prevent, suppress, suppress individual muscle wasting disorder or reduction individuality muscle wasting disorder incidence medicine in application.
21. the application of claim 20, wherein said muscle wasting disorder is caused by pathology, slight illness, disease or illness.
The application of 22. claims 21, wherein said pathology, slight illness, disease or illness are nervosas, infectivity, chronic or genetic.
The application of 23. claims 22, wherein said pathology, slight illness, disease or illness are myatrophy, emaciation, malnutrition, leprosy, diabetes, ephrosis, chronic obstructive pulmonary disease (COPD), Sarcopenia, pulmonary emphysema, osteomalacia, HIV or myocardosis.
The application of 24. claims 22, wherein said pathology, slight illness, disease or illness are muscular dystrophy, the chain ridge bulbar muscular atrophy (SBMA) of X, cancer, end stage Renal failure, AIDS or congestive heart failure (CHF).
The application of 25. claims 20, wherein said muscle wasting disorder is the muscle wasting disorder of being correlated with at the age, useless sexual function degenerates relevant muscle wasting disorder; Or described muscle wasting disorder is caused by chronic lower back pain, burn, central nervous system (CNS) damage or infringement, peripheral nerve injury or infringement, chemical damage or infringement or alcoholism.
The application of 26. claims 20, wherein said muscle wasting disorder is caused by Spinal injury or infringement.
The SARM compound of 27. claims 1 or containing its composition for the preparation of the application increased in the medicine of individual muscle behavior expression, muscle size, muscular strength or its arbitrary combination.
The SARM compound of 28. claims 1 or containing its application of composition in the medicine of the obesity of being correlated with for the preparation of the individual metabolism syndrome for the treatment of or diabetes.
The application of 29. claims 28, wherein said individuality suffers from Hormonal Diseases.
The application of 30. claims 28, wherein said individuality suffers from hormone imbalances or disorder.
The application of 31. claims 29, wherein said individuality is in climacteric.
The application of 32. claims 29, wherein said SARM increases the thin heavy of individuality.
The SARM compound of 33. claims 1 or containing its composition for the preparation of the application promoted or in the spermatogenetic medicine of compacting male individual.
Application any one of 34. claims 9 or 11, wherein said compound is 3 to 1 with the ratio of described Alendronate.
Application any one of 35. claims 5,10,17,18,20,27,28 or 33, wherein said medicine gives through intravenously, intra-arterial or intramuscular in liquid form; Be implanted subcutaneously in described individuality with pellet form; Give so that liquid or solid form is oral; Give so that liquid or solid form is sublingual; Or described medicine is locally applied to the mucomembranous surface of described individuality.
Application any one of 36. claims 5,10,17,19,20,27,28 or 33, wherein said medicine is pill, tablet, capsule, solution, suspensoid, emulsion, elixir, gelifying agent, emulsifiable paste, suppository or parenteral administration.
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US10/863,524 US20050038110A1 (en) 2000-08-24 2004-06-09 Selective androgen receptor modulators and methods of use thereof
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US10/961,380 US20060019931A1 (en) 2003-10-14 2004-10-12 Treating bone-related disorders with selective androgen receptor modulators
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