CN102976973A - Selective androgen receptor modulator and method for using thereof - Google Patents

Selective androgen receptor modulator and method for using thereof Download PDF

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CN102976973A
CN102976973A CN2012105104648A CN201210510464A CN102976973A CN 102976973 A CN102976973 A CN 102976973A CN 2012105104648 A CN2012105104648 A CN 2012105104648A CN 201210510464 A CN201210510464 A CN 201210510464A CN 102976973 A CN102976973 A CN 102976973A
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sarm
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CN102976973B (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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Priority claimed from US10/961,380 external-priority patent/US20060019931A1/en
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Abstract

The invention relates to a selective androgen receptor modulator and a method for using thereof. Specifically, the invention provides a SARM compound and application of treating various diseases or illnesses in individuals. The diseases or illnesses especially comprise muscle marasmus diseases or illnesses or bone related diseases or illnesses.

Description

SARM and using method thereof
The application submitted on June 7th, 2005, and denomination of invention is divided an application for the Chinese patent application 200580018468.2 of " SARM and using method thereof ".
Background technology
Androgen receptor (" AR ") is the transcription regulatory protein that part activates, and it is induced by its endogenous androgenic activity mediation Male sexual growth and function.Male sex hormone is commonly called male sex hormone.Male sex hormone is to be produced in vivo by testis and adrenal cortex, the steroid that perhaps can synthesize in the laboratory.Androgenic steroids plays an important role in many physiological processs, comprise the growth of male sex characteristics such as muscle and bone amount and keep, prostate gland growth, spermatogeny and male sex's hair distribute (Matsumoto, Endocnnol.Met.Clin.N.Am.23:857-75 (1994)).Endogenous steroid male sex hormone comprises testosterone and dihydrotestosterone (" DHT ").Testosterone is the main steroid by testicular secretion, and is the main circulation male sex hormone of finding in male sex's serum.In many peripheral tissues, testosterone is changed into DHT by the enzyme 5α-reductase.Therefore think that for most of androgenic effects, DHT plays a part medium in born of the same parents people such as (, Molec.Endocrinol.9:208-18 (1995)) Zhou.Other steroid male sex hormone comprises the ester of testosterone, such as cipionate, propionic ester, phenylpropionic acid ester, cyclopentanepropanoiacid acid ester, isocarporate, heptanoate and decylate, and other synthetic androgen, such 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 participating in Male sexual, AR grows and function, so AR is likely the target of the hormone replacement therapy of realizing male contraception or other form.
The BMD of masculinity and femininity (bone mineral density) all reduces with the growth at age.The slippage of bone mineral content (BMC) and BMD and bone strength reduction have dependency, make the patient be easy to fracture.
Osteoporosis is a kind of systemic skeletal diseases, it is characterized by low bone amount, osseous tissue degeneration, and the result increases bone fragility and is easy to fracture.In the U.S., there is the people 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 spine fracture, 250000 routine hip fractures and 240000 routine fracture of the carpal bone.Hip fracture is the osteoporosis severest consequences, causes individual death, the maimed person of the survivor more than 50% of 5-20% every year.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 will 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 in-seam loss in 5 years after menopause is obviously accelerated.Other factor that increases this risk comprises mode of life and the absorption of low calcium of smoking, alcohol abuse, sitting.Yet osteoporosis also often occurs in the male sex.Determine that clearly male sex's bone mineral density reduces with the age increase.The minimizing of bone mineral content and amount of densities is relevant with the bone strength reduction, and is easy to fracture.The molecule mechanism of sexual hormoue pleiotropic effects in non-germinal tissue has just begun to be familiar with, but male sex hormone and estrogenic physiological concentration are clearly to keeping the bone stable state to play an important role in whole life cycle.Therefore, when male sex hormone or oestrogenic hormon forfeiture generation, consequently bone remodeling speed increases, and the balance that absorbs and form is tilted for being conducive to absorption, and this causes whole bone amount loss.In the male sex, the naturally minimizing (androgenic direct minimizing and the lower estrogen level derived from androgenic periphery aromizing) of maturity hormone is relevant with bone fragility.This effect is also observed in the castrating male sex.
Wasting disease 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 and degeneration of unstriated muscle of controls movement.Chronic wasting disease 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 muscle mass loss that occurs during wasting disease can be that myoprotein decomposes degraded.It is unusual high protein degradation speed, unusual low protein synthesis rate, the perhaps combination of the two that protein decomposes the reason that occurs.The myoprotein degraded no matter be to be caused or caused by the synthetic degree of lower protein by the high protein degree of degradation, all cause the muscle mass minimizing and causes wasting disease.
Wasting disease is relevant with chronic, nervosa, heredity or infectivity pathology, disease, slight illness or illness.These comprise muscular dystrophy, such as bulbar paralysis muscular dystrophy and myotonia atrophica; Myatrophy is such as myatrophy after the poliomyelitis (PPMA); Emaciation reduces disease (sarcopenia), pulmonary emphysema, osteomalacia, HIV infection, AIDS and myocardosis such as heart emaciation, AIDS emaciation and cancer cachexia, malnutrition, leprosy, diabetes, ephrosis, chronic obstructive pulmonary disease (COPD), cancer, renal failure in latter stage, muscle.
In addition, other environment is relevant with wasting disease with illness, and can cause wasting disease.These comprise chronic 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, because ailing or damage causes that four limbs are fixed, uselessly degenerating (disuse deconditioning) with sexual function of occuring during long-term inpatients, and alcoholism.
Complete androgen receptor (AR) signal pathway plays a crucial role for the suitable growth of skeletal muscle.And, complete AR-signal pathway increase thin heavy, the muscular strength of muscle and myoprotein synthetic.
If the unabated words of wasting disease may have fearful health consequences.For example, the variation that occurs during wasting disease may cause physical appearance to die down, and this health to individuality is harmful, causes the susceptibility increase and the behavior state that infect bad.In addition, wasting disease is the strong predictor of suffering from emaciation and AIDS patient's M ﹠ M.
Basic science level and clinical level all are badly in need of a kind of method of initiative with prevention and treatment osteoporosis and other bone photo related disorders and wasting disease, particularly chronic wasting disease.The present invention satisfies this needs.
Summary of the invention
In one embodiment, the invention provides a kind of SARM (SARM) compound or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination that is represented by the structure of formula (I):
Figure BDA00002515436200031
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 be 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 1Be CH 3, CH 2F, CHF 2, CF 3, CH 2CH 3Or CF 2CF 3
In another embodiment, the invention provides SARM (SARM) compound or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination by the representative of the structure of formula (III):
Figure BDA00002515436200041
In another embodiment, the invention provides SARM (SARM) compound or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination by the representative of the structure of formula (IV):
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:
Figure BDA00002515436200043
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 1Be CH 3, CH 2F, CHF 2, CF 3, CH 2CH 3Or CF 2CF 3
In one embodiment, according to this aspect of the present invention, X is O, and perhaps in another embodiment, T is OH, perhaps in another embodiment, and R 1Be CH 3, perhaps in another embodiment, Z is NO 2, perhaps in another embodiment, Z is CN, perhaps in another embodiment, and R 2, R 3, R 5, R 6Be H, and R 4Be NHCOCF 3, perhaps in another embodiment, R 2, R 3, R 5, R 6Be H, and R 4Be F, perhaps in another embodiment, R 2, R 3, R 5, R 6Be H, perhaps in another embodiment, Z is in contraposition, and perhaps in another embodiment, Y is in a position, perhaps in another embodiment, and their arbitrary combination.
In another embodiment, the invention provides a kind of pharmaceutical composition, it contains formula (I), (III) or SARM compound (IV) and suitable carrier or thinner.
In another embodiment, the composition that the invention provides formula (I), (III) or compound (IV) or contain it suffers from application in the individuality of bone photo related disorders in treatment.
In another embodiment, the composition that the invention provides formula (I), (III) or compound (IV) or contain it is increasing individual bone strength or bone amount or is promoting application in the individual bone forming.
In another embodiment, the invention provides formula (I), (III) or compound (IV) is used for the treatment of, prevents, suppresses, suppresses individual wasting disease or reduce application in the incidence of individual wasting disease.
In another embodiment, the invention provides formula (I), (III) or compound (IV) in the application that increases individual muscle behavior performance, muscle size, muscular strength or its arbitrary combination.
In another embodiment, the composition that the invention provides formula (I), (III) or compound (IV) or contain it is in the relevant obesity of the individual metabolism syndrome for the treatment of or the application in the diabetes.
In another embodiment, the application during the composition that the invention provides formula (I), (III) or compound (IV) or contain it recovers after promoting or accelerating operation technique.
In another embodiment, the composition that the invention provides formula (I), (III) or compound (IV) or contain it promote or the spermatogeny of compacting male individual in application.
Description of drawings
Fig. 1: SARM, DHT and PTH are to the effect of rat bone marrow cell to the differentiation of scleroblast system.
Fig. 2: SARM, DHT and PTH are to the effect of the positive multinucleated osteoclast of TRAP.
Fig. 3: the femur overall loading that 3 bending methods of femur are measured.
Fig. 4:PQCT analyzes the trabecular bone mineral density of the distal femoral of measuring.
Fig. 5: the pharmacology of compound III in intact rats.
Fig. 6: the organ weight of the castrating rat that compound III is processed represents with the per-cent of complete contrast.* the complete contrast of P value<0.05vs..
Fig. 7: organ weight's preservation dose-response curve of compound III in the castrating rat.The E of musculus levator ani (closed triangle), prostate gland (open loop) and seminal vesicle (closed square) MaxAnd ED 50Value is by using
Figure BDA00002515436200061
In sigmoid curve E MaxModel carries out nonlinear regression analysis and obtains.
Fig. 8: the organ weight of the castrating rat that compound III is processed represents with complete per-cent to group.* the complete contrast of P value<0.05vs..
Fig. 9: the organ weight of the compound III dose-response curve of regenerating in the castrating rat.The E of musculus levator ani (closed triangle), prostate gland (open loop) and seminal vesicle (closed square) MaxAnd ED 50Value is by using
Figure BDA00002515436200062
In sigmoid curve E MaxModel carries out nonlinear regression analysis and obtains.
Figure 10: the oral serum-concentration-time plot that gives the compound III in PEG300 among the healthy volunteer.
Figure 11: the serum-concentration-time plot of compound III solution vs. solid oral dosage form.
Figure 12: the different dosage form of compound III is with the serum-concentration-time plot 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: the cholesterol of compound III reduces in the rat.
Embodiment
In following embodiment, for providing the present invention is understood completely, set forth many specific details.But it will be understood by those skilled in the art that does not have these specific details the present invention can be put into practice yet.In other cases, be limited in order not make the present invention, known method, step and component are not described in detail.
In one embodiment, the invention provides a kind of SARM (SARM) compound or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination that is represented by the structure of formula (I):
Figure BDA00002515436200071
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 be 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 1Be CH 3, CH 2F, CHF 2, CF 3, CH 2CH 3Or CF 2CF 3
In another embodiment, the invention provides SARM by the representative of the structure of formula (II):
Figure BDA00002515436200072
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 or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination by the representative of the structure of formula (III):
Figure BDA00002515436200081
In another embodiment, the invention provides SARM (SARM) compound or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination that is represented by formula (IV) structure:
Figure BDA00002515436200082
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:
Figure BDA00002515436200083
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 1Be CH 3, CH 2F, CHF 2, CF 3, CH 2CH 3Or CF 2CF 3
In one embodiment, according to this aspect of the present invention, X is O, and perhaps in another embodiment, T is OH, perhaps in another embodiment, and R 1Be CH 3, perhaps in another embodiment, Z is NO 2, perhaps in another embodiment, Z is CN, perhaps in another embodiment, and R 2, R 3, R 5, R 6Be H, and R 4Be NHCOCF 3, perhaps in another embodiment, R 2, R 3, R 5, R 6Be H, and R 4Be F, perhaps in another embodiment, R 2, R 3, R 5, R 6Be H, perhaps in another embodiment, Z is in contraposition, and perhaps in another embodiment, Y is in a position, perhaps in another embodiment, and their arbitrary combination.
In one embodiment, the invention provides a kind of pharmaceutical composition, it contains formula (I), (II), (III) or compound (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 and replace by one or more: halogen, hydroxyl, carbalkoxy, amido, alkyl amido, dialkyl group amido, 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 pairs of keys.Thiazolinyl can have two keys, two two keys, three two keys etc.The example of thiazolinyl is vinyl, propenyl, butenyl, cyclohexenyl etc.Thiazolinyl can be unsubstituted or is selected from following group and replace by one or more: halogen, hydroxyl, carbalkoxy, amido, alkyl amido, dialkyl group amido, nitro, amino, alkylamino, dialkyl amido, carboxyl, sulfo-and alkylthio.
" haloalkyl " refers to the alkyl of above definition, and it is replaced by one or more halogen atoms, in one embodiment, replaced by F, in another embodiment, replaced by Cl, in another embodiment, replaced by Br, in another embodiment, replaced by I.
" aryl " refers to have the aromatic group of at least one isocyclic aryl or heterocyclic aryl, and it can be unsubstituted or is selected from following group and replace by one or more: halogen, haloalkyl, hydroxyl, carbalkoxy, amido, alkyl amido, dialkyl group amido, 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 the OH group.It will be appreciated by those skilled in the art that when the T in the compound of the present invention is OR R is not OH.
In one embodiment, term " halogen (halo) " or " halogen (halogen) " refer to refer in another embodiment Cl by F in one embodiment, refer in another embodiment Br, or refer in another embodiment I.
In one embodiment, " aralkyl " refers to the alkyl that is connected with aryl, and wherein alkyl and aryl as above define.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 that contains the SARM compound, the combination of analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicine, hydrate, N-oxide compound, prodrug, polymorphic form, impurity or the crystal of SARM compound of the present invention is provided perhaps in another embodiment.
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 comprise the optically active isomer of 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 that uses in the method for the present invention can exist with optically-active form or racemic form, also can be separated into optically-active form 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 that is used for the treatment of male sex hormone associated 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 (R) and (S) mixture of isomer.In another embodiment, SARM contains equivalent (R) and (S) racemic mixture of isomer.Well known in the art how to prepare the optically-active form (for example by recrystallization technology resolution of racemic form, by synthetic from the optically-active raw material, by chirality synthetic or by using chiral stationary phase to carry out chromatographic separation).
The present invention includes SARM of the present invention " pharmacologically acceptable salts ", can use in one embodiment amino SARM and the organic and mineral acid that replaces, for example citric acid and hydrochloric acid prepare described pharmacologically acceptable salts.In another embodiment, pharmacologically acceptable salts can also be by preparing with mineral alkali such as sodium-hydroxide treatment phenolic compound.In another embodiment, can be by prepare the ester of phenolic compound with aliphatic series and aromatic carboxylic acid such as acetic acid and benzoic ether.
The present invention also comprises the amino substituent N-oxide compound 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 by any material of another kind of material by metabolism or metabolic process generation.
In other embodiments, the present invention also provides the medicine of SARM compound.In other embodiments, term " medicine " refers to the composition (pharmaceutical composition) that is suitable for pharmaceutical application as described herein.
Selective androgen conditioning agent (SARM)
SARM (SARM) is a class androgen receptor target agent (ARTA), and they show short hero and the anabolic activity of the on-steroidal part of androgen receptor.These new promoting agents are used for the relevant illness of the various hormones of male treatment such as sexual dysfunction, sexual desire reduction, erective dysfunction, hypogonadism, muscle minimizing disease, 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 hormones such as sexual dysfunction, sexual desire reduction, hypogonadism, muscle minimizing disease, osteopenia, osteoporosis, cognition and mood change, depression, anaemia, alopecia, obesity, endometriosis, breast cancer, uterus carcinoma and ovarian cancer for the women.
Consider such as this paper, the invention provides class SARM (SARM) compound.These compounds that are used for prevention and treatment wasting disease and bone photo related disorders are classified as androgen receptor agonist (AR agonist), partial agonist or androgen receptor antagonists (AR antagonist).
Receptor stimulant be bind receptor and activation material.Acceptor portion agonist be bind receptor and the part activation material.Receptor antagonist is bind receptor and the material that makes it inactivation.Such as this paper institute illustration, in some embodiments, SARM compound of the present invention has the tissue selectivity effect, and for example wherein single promoting agent is agonist, partial agonist and/or antagonist, and this depends on the tissue that this receptor is expressed.For example, but SARM compound stimulated muscle tissue and suppress simultaneously prostata tissue.In one embodiment, being used for the treatment of and preventing the SARM of wasting disease is agonist, therefore is used for combination and activates AR.Therefore in another embodiment, SARM is the AR antagonist, is used in conjunction with AR and makes the AR inactivation.Determine that compound of the present invention is that AR agonist or the assay method of antagonist are known for a person skilled in the art.For example, the AR agonist activity can keep and/or stimulates the ability of the growth of the tissue that contains AR such as prostate gland and seminal vesicle to determine by adopting weight determination to monitor the SARM compound.The AR antagonistic activity can contain by monitoring the inhibition of SARM compound the ability of the growth of AR tissue and determine.
In another embodiment, SARM compound of the present invention can classify as part AR agonist/antagonist.SARM is the AR agonist in some tissues, causes the AR-reactive group to transcribe increase (for example muscle anabolic action).In other tissue, these compounds are as the competitive inhibitor of testosterone/DHT to AR, to stop endogenous androgenic agonism.In one embodiment, term SARM or SARM refer to regulate the compound of estrogen receptor activity.In one embodiment, SARM is agonist, perhaps in another embodiment, is antagonist.
In one embodiment, SARM has antagonistic activity in the sexual gland of individuality, and for example has agonist activity in the muscle in periphery.This paper has just proved these activity to the effect of prostata tissue than the effect aspect of musculus levator ani muscle tissue, as illustrated among Fig. 3,4 or 5.
In one embodiment, SARM compound of the present invention is reversibly in conjunction with androgen receptor, perhaps in another embodiment, and irreversibly in conjunction with androgen receptor.In one embodiment, the SARM compound is reversibly in conjunction with androgen receptor.In another embodiment, the SARM compound is irreversibly in conjunction with androgen receptor.Compound of the present invention can contain the functional group's (for example affinity tag) that makes androgen receptor alkylation (being the covalent linkage form).Therefore, in the case, this compound is bind receptor irreversibly, thereby can not be substituted by steroid such as endogenic ligand DHT and testosterone.
In one embodiment, the adjusting of androgen receptor refer to compound by acceptor and in another embodiment arbitrary the or all downstream effects by receptor signal conduction stimulate or the ability of enhancing signal conduction.
In another embodiment, the adjusting of androgen receptor refer to compound by acceptor and in another embodiment arbitrary the or all downstream effects by receptor signal conduction weaken 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 on the structure in one embodiment, perhaps refers in another embodiment acceptor relevant on the function, and the adjusting of this receptor is expected.SARM of the present invention can interact with estrogen receptor in one embodiment, perhaps in another embodiment, interact with other cell surface molecule that participates in route of synthesis, perhaps in another embodiment, interact with other cell surface molecule that participates in the Steroidgenesis approach, perhaps in another embodiment, interact with other cell surface molecule that participates in pathways metabolism.
In one embodiment, the present invention also provides the composition that contains a kind of SARM of the present invention, perhaps in another embodiment, contains the composition of 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, the micronization capsule contains the particle that comprises SARM of the present invention, and wherein term used herein " micronization " refers to that particle diameter is less than 100 microns particle, in another embodiment, less than 50 microns, perhaps in another embodiment, less than 35 microns, perhaps in another embodiment, less than 15 microns, perhaps in another embodiment, less than 10 microns, perhaps in another embodiment, less than 5 microns.
Described pharmaceutical composition can with any effectively, mode gives easily, for example give or give by any mode (for example pin or conduit) that recombinant virus/composition can be delivered to tissue by sending in (i.n.), subcutaneous (s.c.) in (i.v.), intramuscular (i.m.), the nose in the blood vessel, hypogloeeis, oral, rectum, the sheath.Perhaps, topical can expect to be applied to mucomembranous cell, uses for skin or eye.Another kind of administering mode is to give through inhalation or aerosol formulation.
For giving Mammals, people particularly, expection doctor will determine during actual dosage and the treatment, be only for individuality during described dosage and the treatment, and may change with unique individual's age, body weight and reaction.
In one embodiment, the composition that gives can be sterile solution, perhaps 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 such 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 contain sterilized water or any other sterile injectable medium.
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 one or more compounds of the present invention of significant quantity and be used for suitable excipient and/or the carrier of method of the present invention.In one embodiment, described composition will contain the SARM of the present invention that treats 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 give by any method known in the art.
In one embodiment, composition of the present invention is mixed with oral or parenteral dosage forms, such 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 ointment, emulsifiable paste or the gel form for percutaneous dosing.In another embodiment, compound of the present invention is mixed with aerosol or the sprays for 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 or suspensoid in the ester, 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 type of using 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 contain suitable binder, lubricant, thinner, disintegrating agent, tinting material, seasonings, flow-induction agent and fusing agent.For example liquid dosage form can contain suitable solvent, sanitas, emulsifying agent, suspending agent, thinner, sweeting agent, thickening material and fusing agent.Parenteral and intravenously form also comprise mineral substance and other material so that they and selected injection or delivery system type are compatible.Certainly, also can use other vehicle.
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, perhaps in another embodiment, 0.1-25mg, perhaps in another embodiment, 0.1-50mg, perhaps in another embodiment, 0.3-15mg, perhaps in another embodiment, 0.3-30mg, perhaps in another embodiment, 0.5-25mg, perhaps in another embodiment, 0.5-50mg, perhaps in another embodiment, 0.75-15mg, perhaps in another embodiment, 0.75-60mg, perhaps in another embodiment, 1-5mg, perhaps in another embodiment, 1-20mg, perhaps in another embodiment, 3-15mg, perhaps in another embodiment, 30-50mg, perhaps in another embodiment, 30-75mg, perhaps 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 can be used for any method of the present invention.In one embodiment, as skilled in the art will understand, SARM or contain its being applied in inhibition, compacting, increasing or stimulating in the reaction of expecting in the individuality useful of composition.In another embodiment, described composition also can contain other activeconstituents, and the activity of described other activeconstituents is useful for the application-specific that the SARM compound is just giving.
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 and be used for following application: 1) treatment bone photo related disorders; 2) prevention bone photo related disorders; 3) compacting bone photo related disorders; 4) suppress the bone photo related disorders; 5) increase individual bone strength; 5) increase individual bone amount; 6) being used for suppressing osteoclast generates.In one embodiment, the described SARM compound compound that is formula I as herein described, II, III or IV.
In one embodiment, described bone photo related disorders is heredopathia, and perhaps in another embodiment, described bone photo related disorders is as the result of the treatment plan of given disease and be caused.For example in one embodiment, SARM of the present invention is used for the treatment of the bone photo related disorders, and described bone photo related disorders is caused as the result of the androgen-deprivation treatment that given prostate cancer in the individuality is reacted.
In one embodiment, the invention provides the application that the SARM compound is used for preventing individuality bone photo related disorders.In another embodiment, the invention provides the application that the SARM compound is used for compacting individuality bone photo related disorders.In another embodiment, the invention provides the application that the SARM compound is used for suppressing individuality bone photo related disorders.In another embodiment, described SARM compound is formula (I), (II), (III) or compound (IV).In another embodiment, described SARM compound is formula (I), (II), (III) or compound (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 photo related disorders is osteoporosis.In another embodiment, described bone photo related disorders is osteopenia.In another embodiment, described bone photo related disorders is that bone resorption increases.In another embodiment, described bone photo related disorders is fracture.In another embodiment, described bone photo related disorders is that bone is fragile.In another embodiment, described bone photo related disorders is that BMD reduces.In another embodiment, described bone photo related disorders is the arbitrary combination that osteoporosis, osteopenia, bone resorption increase, fracture, bone fragility and BMD reduce.Every kind of illness all represents independent embodiment of the present invention.
In one embodiment, " osteoporosis " refers to that bone that the exhaustion owing to calcium and bone protein causes attenuates and the bone amount reduces.In another embodiment, osteoporosis is a kind of systemic skeletal diseases, it is characterized in that low bone amount and osseous tissue degeneration, and as a result bone fragility increase also is easy to fracture.In one embodiment, the bone strength of sufferers of osteoporosis face is unusual, and the risk that causes fracturing increases.In another embodiment, osteoporosis is exhausted the calcium of normal presence in the bone and Protocollagen, causes in one embodiment the unusual or bone density decline of sclerotin.In another embodiment, do not cause under normal conditions slightly falling down or damage just may make and getting involved in osteoporotic osteogenesis fracture of fracture.In one embodiment, fracture can be the form (such as hip fracture) of crackle or the form (such as the compression fracture of backbone) of subsiding.Spine, hipbone and carpal bone are the zones of the common generation of the fracture that causes of osteoporosis, but other bony areas also can be fractured.In another embodiment, osteoporosis can cause posture change, physical abnormality and handiness to reduce without inhibition.
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 that teenager's sclerotin is loose.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.Every type osteoporosis all represents independent embodiment of the present invention.
In another embodiment, osteoporosis and osteopenia are systemic skeletal diseases, it is characterized by low bone amount and osseous tissue microstructure and degenerate.In one embodiment, " microstructure degeneration " connection of referring to attenuate bone trabecula (the following definition) being connected with bone trabecula is lost.In another embodiment, " osteoporosis " is defined as BMD and is lower than 2.5 standard deviations (SD) of Young Adults mean value or lower.In another embodiment, " osteoporosis " is defined as BMC and is lower than the 2.5SD of Young Adults mean value or lower.In another embodiment, " osteoporosis " is defined as BMD and is lower than the 2.0SD of Young Adults mean value or lower.In another embodiment, " osteoporosis " is defined as BMC and is lower than the 2.0SD of Young Adults mean value or lower.In another embodiment, " osteoporosis " is defined as BMD and is lower than the 3.0SD of Young Adults mean value or lower.In another embodiment, " osteoporosis " is defined as BMC and is lower than the 3.0SD of Young Adults mean value or lower.Osteoporosis or osteopenic every kind of definition all represent independent embodiment of the present invention.
In another embodiment, " osteoporosis " is defined as the 2.5SD that BMD is lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 2.5SD that BMC is lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 2.0SD that BMD is lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 2.0SD that BMC is lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 3.0SD that BMD is lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 3.0SD that BMC is lower than Young Adults mean value.Osteoporotic every kind of definition all represents independent embodiment of the present invention.
It is well known in the art estimating osteoporosis and osteopenic method.For example, in one embodiment, with the densitometry measurement and with g/cm 2The patient's of expression BMD compares with " normal value " and obtains " T value (T score) ", and this normal value is the mean value of the Young Adults peak bone mass of gender matched.In another embodiment, patient's bone loss amount is obtained Z value (Z-score) with comparing with others' group's of the age same sex expectation amount lost.In another embodiment, " osteoporosis " is defined as the T value and is lower than the 2.5SD of Young Adults mean value or lower.In another embodiment, " osteoporosis " is defined as the Z value and is lower than the 2.5SD of Young Adults mean value or lower.In another embodiment, " osteoporosis " is defined as the T value and is lower than the 2.0SD of Young Adults mean value or lower.In another embodiment, " osteoporosis " is defined as the Z value and is lower than the 2.0SD of Young Adults mean value or lower.In another embodiment, " osteoporosis " is defined as the T value and is lower than the 3.0SD of Young Adults mean value or lower.In another embodiment, " osteoporosis " is defined as the Z value and is lower than the 3.0SD of Young Adults mean value or lower.
In another embodiment, " osteoporosis " is defined as the 2.5SD that the T value is lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 2.5SD that the Z value is lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 2.0SD that the T value is lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 2.0SD that the Z value is lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 3.0SD that the T value is lower than Young Adults mean value.In another embodiment, " osteoporosis " is defined as the 3.0SD that the Z value is lower than Young Adults mean value.Osteoporotic every kind of definition all represents independent embodiment of the present invention.
In one embodiment, term " BMD " refers to the measurement calculated value of actual bone amount.The absolute magnitude of the bone of being measured by BMD usually and bone strength and weight capacity thereof have dependency.As the risk that Measure blood pressure can help to predict apoplexy, can predict the risk that fracture occurs by measuring BMD.
In one embodiment, BMD can survey and draw by BMD (mapping) commercial measurement.In one embodiment, the bone density of hipbone, spine, carpal bone or calcaneum can be measured by multiple technologies.The preferred method of measuring BMD is dual-energy x-ray Osteodensitometry (DEXA).Can use the BMD of this commercial measurement hipbone, front and back (AP) spine, side position vertebra and carpal bone.The measurement at arbitrary position can both be predicted the overall risk that fracture occurs, but is the best information of this position fracture of prediction from the information that privileged site obtains.Quantitative Analysis machine control tomography (QCT) also is used for measuring the BMD of spine.Referring to such as " Nuclear Medicine: " Quantitative Procedures " Walmer H W etc., Toronto Little, Brown﹠amp; Co. publish 1983, the 107-132 pages or leaves; " Assessment ofBone Mineral Part 1, " J Nucl Medicine, pp1134-1141 (1984); And " BoneMineral Density of The Radius " J Nucl Medicine 26:13-39 (1985).Every kind of method measuring BMD all represents independent embodiment of the present invention.
In one embodiment, " osteopenia " refers to that BMD or BMC are lower than the 1-2.5SD of Young Adults mean value.In another embodiment, " osteopenia " phalanges calcification or Decrease of Bone Mineral Density.In one embodiment, all Skeletal systems that this illness is arranged contained in this term.Every kind of illness disclosed by the invention definition or diagnostic method all represent independent embodiment of the present invention.
In one embodiment, term " fracture " phalanges breaks, and comprises fractured spinal bones and non-fractured spinal bones.In one embodiment, term " bone fragile " the fragile state of instigating bone to be easy to fracture.
In one embodiment, described bone photo related disorders is with SARM compound of the present invention or its combined therapy.In another embodiment, can be before giving one or more SARM of the present invention, simultaneously or offer afterwards individual other spur and intensify compound.In one embodiment, described spur intensifies compound and can contain natural or synthetic material.
In one embodiment, as the skilled artisan will appreciate, described spur intensifies compound can comprise Delicious peptide (BMP), somatomedin such 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 such as Sonic hedgehog (sonic hedgehog), porcupine albumen (indian hedgehog) and desert hedgehog (desert hedgehog), hormone such as follicle stimulating hormone, Rat parathyroid hormone 1-34, parathyroid hormone-related peptide, activin, statin, frizzled albumen, frzb albumen or frazzled albumen, BMP is in conjunction with albumen such as chordin and Pp63 glycophosphoproteins, cytokine such as IL-3, IL-7, GM-CSF, chemokine such as eotaxin, collagen protein, osteocalcin, osteonectin etc.
In another embodiment, the composition that is 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 spur intensifies compound and gives birth to osteocyte.In one embodiment, giving birth to osteocyte 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, the nucleic acid that coding spur can be intensified compound gives described individuality, thinks that it is a part of the present invention.
In one embodiment, osteoporosis of the present invention, osteopenia, bone resorption increase, fracture, bone fragility, BMD decline and other illness or disease are by hormone disturbance, destruction or unbalance causing.In another embodiment, these illnesss do not rely on hormone disturbance, destruction or unbalance and occur.Every kind of possibility all represents independent embodiment of the present invention.
In one embodiment, described hormone disturbance, imbalance or the unbalance hormone that comprises are excessive.In another embodiment, described hormone disturbance, imbalance or the unbalance hormonoprivia that comprises.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 any other hormone as known in the art.In another embodiment, described hormone disturbance, imbalance or unbalance relevant with menopause.In another embodiment, hormonoprivia is the result as the specific operation of the by product for the treatment of individual disease or illness.For example, described hormonoprivia can be the result who loses as male sex hormone in the individuality that causes of the individual prostate cancer for the treatment of.
Every kind of possibility all represents independent embodiment of the present invention.
In one embodiment, the invention provides the SARM compound for increasing the application of individual bone strength.In another embodiment, described SARM compound is formula (I), (II), (III) or compound (IV).In another embodiment, described SARM compound is formula (I), (II), (III) or compound (IV) or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination.Thereby, 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 SARM compound for increasing the application of individual bone amount.In another embodiment, described SARM compound is formula (I), (II), (III) or compound (IV).In another embodiment, described SARM compound is formula (I), (II), (III) or compound (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 contains 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 muscle minimizing disease 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 the Grafting Cancellous Bone Bolt amount.
In one embodiment, the invention provides the application that the SARM compound is used for promoting bone growing.In another embodiment, described SARM compound is formula (I), (II), (III) or compound (IV).In another embodiment, described SARM compound is formula (I), (II), (III) or compound (IV) or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination, perhaps contains its composition.
In another embodiment, described SARM compound stimulates or is enhanced to osteocyte and generates.In another embodiment, described SARM compound suppresses osteoclast propagation.
In one embodiment, the invention provides the osteogenesis that stimulates or strengthen propagation through scleroblast.In one embodiment, term " scleroblast " refers to participate in osteogenetic cell.In one embodiment, but participate in osteogenetic scleroblast formative tissue, mineral deposit wherein makes bone have intensity.In another embodiment, the invention provides the osteogenesis of inducing through suppressing osteoclast, perhaps in another embodiment, provide through suppressing the osteogenesis of osteoclast activity.In one embodiment, term " osteoclast " refers to participate in bone to be rebuild, particularly the cell of bone resorption.
In one embodiment, osteopathia or illness are treated through the stimulation osteogenesis by method of the present invention.In another embodiment, treatment of the present invention provides the bone amount that keeps.Balance between osteoblastic activity by forming bone and the activity of osteoclastic osteoclast keeps the bone amount.In one embodiment, Compounds and methods for of the present invention provides the method that keeps described balance.
Fig. 1-2 has set forth described SARM compound III and has induced medullary cell to osteoblastic differentiation, and suppresses osteoclast and induce, and shows SARM to the direct effect of scleroblast and osteoclast, and it is useful in increasing 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 and be used for following application: 1) treatment wasting disease; 2) prevention wasting disease; 3) treatment, prevention, compacting, inhibition or minimizing are reduced by the muscle that wasting disease causes; 4) wasting that treatment, prevention, inhibition, minimizing or compacting are caused by wasting disease; And/or 5) the mytolin katabolism that treatment, prevention, inhibition, minimizing or compacting are caused by wasting disease.In one embodiment, described SARM compound is formula as herein described (I), (II), (III) or compound (IV).In another embodiment, the invention provides the composition that contains the SARM compound of the present invention that is useful on methods described herein.
In one embodiment, the invention provides the application that the SARM compound is used for the treatment of the individuality of suffering from wasting disease.In another embodiment, described SARM compound is formula (I), (II), (III) or compound (IV).In another embodiment, described SARM compound is formula (I), (II), (III) or compound (IV) or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination, perhaps contains its composition.Thereby treatment suffers from the individuality of wasting disease.
In another embodiment, the application that is used for the treatment of the individuality of suffering from wasting disease of SARM compound comprises the pharmaceutical composition that contains the SARM compound.In another embodiment, giving step comprises described pharmaceutical composition intravenously, intra-arterial or the intramuscularly of liquid form to described individuality; The piller that will contain described pharmaceutical composition is implanted subcutaneously in the described individuality; Give described individuality with the described drug composition oral of liquid or solid form; Perhaps described pharmaceutical composition is locally applied to the skin surface of described individuality.
Muscle is the body tissue that plays a role mainly as source of strength.The muscle that three types is arranged in vivo: a) skeletal muscle-end of responsible mobile body and the muscle of external region; B) cardiac muscle-cardiac muscle; C) muscle of unstriated muscle-in arterial wall and intestines wall.
The disease of becoming thin herein or illness are defined as at least part of illness or disease that is characterised in that unusual, gradual health, organ or tissue's weight reduce.The illness of becoming thin can be used as pathology, occurs such as the result of cancer or infection, and perhaps it is because physiology or metabolism state exist, as may since fixing the giving up of occuring of long-term bed or four limbs degenerate with sexual function.The illness of becoming thin also may be that the age is relevant.The feature that loses weight that occurs during the illness of becoming thin can be the loss of whole body body weight, and perhaps organ weight's loss is as because the bone that the reduction of tissue protein causes or the loss of muscle mass.
In one embodiment, " wasting (muscle wasting) " used herein or " wasting (muscular wasting) " are used interchangeably, and refer to the gradual loss of muscle mass and/or skeleton or voluntary muscle, the cardiac muscle of control heart and the gradual unable and degeneration of unstriated muscle that muscle comprises controls movement.In one embodiment, described wasting illness or disease are chronic wasting illness or disease." chronic wasting disease " is defined as chronic (namely continuing) the gradual loss of muscle mass and/or the chronic gradual unable and degeneration of muscle at this paper in long-time.
The feature of the muscle mass loss that occurs during wasting disease can be to decompose or degraded through the catabolic myoprotein of myoprotein.The reason that Protein catabolism occurs is unusually high proteolytic degradation speed, unusually low albumen synthesis rate or the combination of the two.Protein catabolism no matter be to be caused or caused by low albumen resultant velocity by the high protein degree of degradation, all causes muscle mass to reduce brownization and wasting disease.Term " katabolism " has implication as known in the art, particularly refers to the energy burning form of thanking.
The result that wasting disease 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 illness that directly or indirectly produces muscle mass consumption (i.e. loss), i.e. wasting disease.
In one embodiment, wasting disease is that individuality suffers from muscular dystrophy in the individuality; Myatrophy; The chain ridge bulbar muscular atrophy of X (SBMA); Emaciation; Malnutritive; Tuberculosis; Leprosy; Diabetes; Ephrosis; Chronic obstructive pulmonary disease (COPD); Cancer; The renal failure in latter stage; Muscle reduces disease; Pulmonary emphysema; Osteomalacia; Or myocardiac result.
In another embodiment, described wasting disease is owing to 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 begin the baby or the Childhood become obviously, other type is until the middle age or just obvious later on.Du Xing Shi MD is modal type, particularly affects children.Myotonia atrophica is that these diseases are modal in the adult.
Myatrophy (MA) is characterised in that wasting or minimizing and muscle mass reduce.For example, MA is the wasting disease that occurs as the part of post poliomyelitis syndrome (PPS) after the poliomyelitis.That described atrophy comprises is unable, muscle fatigue and pain.
The MA of another kind of type is the chain ridge bulbar muscular atrophy of X (SBMA-is also referred to as the Kennedy disease).This disease is caused by the defective of the androgen receptor gene on the X chromosome, only affects the male sex, and in the morbidity of growing up.Because the main cause of disease is the androgen receptor sudden change, so the androgen replacement therapy is not present therapeutic strategy.At present more existing researchs wherein give exogenous testosterone propionate to improve androgen levels, and expectation overcomes androgen insensitivity and anabolic action may be provided.The application that the testosterone of excusing from death reason level replenishes will have limitation and other potential severe complication.
Emaciation be caused by disease or as the weak of the side effect of disease with 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 that occurs in the patient who suffers 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.The Individual Experience of suffering from the relevant myopathy of HIV or myasthenia or becoming thin is lost weight significantly, general or centrality myasthenia, tenderness or myatrophy.
It is a kind of wasting diseases that torments Senile Patients with Chronic Disease that muscle reduces disease, it is characterized in that the minimizing of muscle mass and the forfeiture of function.And the increase of lean mass is relevant with the reduction of the M ﹠ M of some wasting disease.In addition, other environment is relevant with wasting disease with condition, and can cause wasting disease.For example, studies show that in the serious case of chronic low back pain have paravertebral muscles to become thin.
Wasting is also relevant with advanced age.Think general unablely caused by wasting in the old-age group.Along with health is aging, skeletal muscle is increased by the ratio that fibrous tissue replaces.Consequently muscle strength, performance and endurance obviously descend.
Because ailing or long-term inpatients that damage causes or for example also can cause wasting disease with the sexual function degeneration when giving up of occuring fixedly time of limbs.Studies show that and suffer from damage, lasting one-sided wasting arranged among the long-term inpatients patient of chronic pain, burn, wound or cancer that lean mass reduces as a result.
The damage of central nervous system (CNS) or infringement are also relevant with wasting disease.The damage of CNS or infringement for example 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, and compound of the present invention and the composition of available representative embodiment of the present invention are treated.
In one embodiment, the invention provides the SARM compound and be used for preventing the application of individual wasting disease.In another embodiment, described SARM compound is formula (I), (II), (III) or compound (IV).In another embodiment, described SARM compound is formula (I), (II), (III) or compound (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 that contains 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.Thereby, the wasting disease that prevention is individual.
In one embodiment, the invention provides the application that the SARM compound is used for the treatment of the wasting disease relevant with chronic disease.In another embodiment, described SARM compound is formula (I), (II), (III) or compound (IV).In another embodiment, described SARM compound is formula (I), (II), (III) or compound (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 contains its composition.In another embodiment, the application of described SARM compound is the oral described individuality that gives.
In one embodiment, the invention provides the SARM compound and be used for preventing the application of individual wasting disease.In another embodiment, suppress individual wasting disease.In another embodiment, suppress individual wasting disease.In another embodiment, reduce the incidence of individual wasting disease.In another embodiment, described SARM compound is formula (I), (II), (III) or compound (IV).In another embodiment, described SARM compound is formula (I), (II), (III) or compound (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 contains 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 contain the application that its composition is used for the treatment of, prevents, suppresses, suppresses individual wasting disease or reduces the incidence of individual wasting disease.
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 contain its application of composition in increasing individual muscle behavior performance, muscle size, muscular strength or its arbitrary combination.
In another embodiment, the recovery after SARM compound of the present invention and composition are used for promotion or accelerate operation technique.
In one embodiment, the invention provides the SARM compound for reducing the application of individual Fat distribution.In another embodiment, described SARM compound is formula (I), (II), (III) or compound (IV).In another embodiment, described SARM compound is formula (I), (II), (III) or compound (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 contains its composition.
In another embodiment, the invention provides SARM compound of the present invention, for example have compound or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination of formula (I), (II), (III) or structure (IV), or the composition that contains it is in the individual obesity relevant with metabolism syndrome for the treatment of or the application in the 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 the SARM compound for increasing the thin heavy application of individuality.In another embodiment, described SARM compound is formula (I), (II), (III) or compound (IV).In another embodiment, described SARM compound is formula (I), (II), (III) or compound (IV) or its prodrug, analogue, isomer, metabolite, derivative, pharmacologically acceptable salts, medicine, polymorphic form, crystal, impurity, N-oxide compound, hydrate or its arbitrary combination.Thereby, 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 that compound III is excito-anabolic and has minimum short male actively that thereby these compounds can be used for treating, and wherein pass by male sex hormone be the patient group who avoids.No matter proved testosterone whether in the presence of the equal stimulated muscle growth of compound III, simultaneously to prostate gland performance antiproliferative effect, thereby in one embodiment, SARM of the present invention recovers the muscle mass that muscle reduces disease or emaciation patient's forfeiture.
In one embodiment, SARM of the present invention is administered to individual intravenous administration through the described pharmaceutical composition with liquid form.In another embodiment, SARM of the present invention is administered to individual intra-arterial administration through the described pharmaceutical composition with liquid form.In another embodiment, SARM of the present invention is administered to individual intramuscular administration through the described pharmaceutical composition with liquid form.In another embodiment, SARM of the present invention implants individual subcutaneous administration through the piller that will contain described pharmaceutical composition.In another embodiment, SARM of the present invention gives individual oral administration by the described pharmaceutical composition with the liquid or solid form.In another embodiment, SARM of the present invention is through being applied to described pharmaceutical composition individual skin surface topical.
In one embodiment, the invention provides safety and effectively be used for the treatment of, prevent, suppress, suppress or reduce muscle loss and/or the catabolic method of mytolin that causes because of wasting disease.In another embodiment, the present invention is used for the treatment of and suffers from the individual of wasting disease or in another embodiment, is used for the treatment of the individuality of suffering from the bone photo related disorders.In another embodiment, described individuality is mammalian subject.
In one embodiment, the present invention relates to prevent, suppress, suppress individual fat or reduce the method for individual fat incidence, it comprises and gives described individuality with effectively preventing, suppress, suppress individual 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 fat or that reduce the amount of individual fat incidence.
In one embodiment, SARM compound of the present invention changes individual leptin (leptin) level.In another embodiment, the SARM compound reduces leptin level.In another embodiment, SARM compound of the present invention increases individual leptin level.Known leptin is influential to the appetite of obesity mice, makes weight saving, so it is with fat relevant.
In one embodiment, SARM of the present invention affects the cyclical level of leptin, perhaps in one embodiment, affects the level of organizing of leptin.In one embodiment, term " leptin level " refers to the serum level of leptin.Consider all leptin is had effect in the external and body of SARM compound of the present invention such as this paper.Leptin level can be measured with method known to those skilled in the art, for example measures by the ELISA test kit of commercially available acquisition.In addition, leptin level can be determined through external test or in vivoassay by any method known to those skilled in the art.
Because leptin participates in appetite control, weight saving, food intake and energy expenditure, therefore regulate and/or the control leptin level in treatment, prevention, suppress to suffer from the fat of fat individuality or reduce that to suffer from the fat individual fat incidence be useful methods for the treatment of.The level of regulating leptin can cause individual appetite decline, food intake minimizing and energy expenditure to increase, thereby may help control and treat fat.
In one embodiment, term " obesity " is defined as the increase of body weight above the restriction of bone and somagenic need, and the result is in vivo excessive buildup of fat.
In one embodiment, term " fat relevant metabolic disorder " refer to that obesity causes, increase the weight of as result, the obesity of obesity 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 main non-inflammation that occurs in the elderly, it is characterized in that sex change, hyperostosis and the synovial membrane edge of joint cartilage and synovial membrane change.In another embodiment, it is attended by pain and stiff, particularly after the 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 repeatedly hypertension more than 140/90mmHg.Chronic hypertension can cause optical fundus blood vessel to change, cardiac muscle thickens, renal failure and cerebral lesion.
In other embodiments, term " apoplexy " refers to usually the infringement of the brain nervous cell that causes because of blood supply insufficiency that angiorrhexis or blood clot cause.In other embodiments, term " heart trouble " refers to heart normal function and active dysfunction, comprises cardiac failure.
In addition, proved recently male sex hormone participate between the matter pluripotent cell be orientated myogenous cells system and stop and be divided into adipose cell lines (2003, Jul 24 for Singh etc., Endocrinology).Therefore, the SARM compound can be used for blocking-up steatogenesis as described herein and/or changes in the method for differentiation of stem cells.
In another embodiment, the present invention relates to the method that promotes, increase or help whose body weight to alleviate, it comprises and will effectively promote, increase or help the SARM of the present invention (SARM) of the amount that whose body weight alleviates and/or the step that 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 reduce, suppress, suppress or reduce the method for individual appetite, it comprises and will effectively reduce, suppresses, suppress or reduce the SARM of the present invention (SARM) of amount of individual appetite and/or the step that 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 change the method for individual body composition, it comprises and will effectively change the SARM of the present invention (SARM) of amount of individual body composition and/or the step that 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 lean mass, fat free body weight or their combination that changes individuality.
In another embodiment, the present invention relates to change the method for individual lean mass or fat free body weight, it comprises and will effectively change the SARM of the present invention (SARM) of amount of individual lean mass or fat free body weight and/or the step that 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 body fat is converted into the method for lean meat, it comprises and will effectively individual body fat be converted into the SARM of the present invention (SARM) of amount of lean meat and/or the step that 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 treat the method for the fat metabolic disorder of being correlated with of individuality, it comprises the SARM of the present invention (SARM) of the amount of the metabolic disorder that effectively the individual obesity for the treatment of is relevant and/or the step that 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 prevent, suppress, suppress or reduce the method for individual fat relevant metabolic disorder, it comprises and will effectively prevent, suppress, suppress or reduce the SARM of the present invention (SARM) of amount of individual fat metabolic disorder of being correlated with and/or the step that 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, 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 reduce, suppress, suppress or reduce individual lipogenetic method, it comprises and will effectively reduce, suppresses, suppress or reduce the SARM of the present invention (SARM) of individual lipogenetic amount and/or the step that 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 change the method for individual differentiation of stem cells, it comprises and will effectively change the SARM of the present invention (SARM) of amount of individual differentiation of stem cells and/or the step that 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 change the method for individual leptin level, it comprises and will effectively change the SARM of the present invention (SARM) of amount of individual leptin level and/or the step that 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 reduce, suppress, suppress or reduce the method for individual leptin level, it comprises and will effectively reduce, suppresses, suppress or reduce the SARM of the present invention (SARM) of amount of individual leptin level and/or the step that 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, being used for following SARM is formula (I), (II), (III) or (IV) compound of structure representative: a) treatment, prevention, compacting, suppress or reduce fat; B) promote, increase or help and lose weight; C) reduce, suppress, suppress or reduce appetite; D) change body composition; E) change lean mass or fat free body weight; F) fat is converted into lean meat; G) the individual fat relevant metabolic disorder for the treatment of, prevention, compacting, inhibition or minimizing, for example hypertension, osteoarthritis, type ii diabetes, elevation of blood pressure, apoplexy or heart trouble; H) reduce, suppress, suppress or reduce individual steatogenesis; I) change differentiation of stem cells; And/or j) changes leptin level.
In one embodiment, find SARM compound of the present invention in treatment or stop the diabetes progress, perhaps treat in the diabetic symptom useful.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, the 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 whole body fungi infestation, congestive heart failure, gout/hyperuricemia, fat, hypertriglyceridemia, hypercholesterolemia, tetter such as necrobiosis lipoidica diabeticorum (NLD) that fatty liver disease (non-alcoholic fatty liver disease or NASH) and diabetes are relevant, diabetic blister (the diabetic bubble is sick), the dermexanthesis xanthomatosis, refer to sclerosis, dispersivity annular granuloma and acanthosis nigricans.
In one embodiment, the invention provides for following method: a) treatment, prevention, compacting, inhibition atherosclerosis; B) treatment, prevention, compacting, inhibition are because the hepatic injury that fatty deposits causes, it comprises and will effectively treat, prevent or suppress atherosclerosis and because 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 of the amount of the hepatic injury that causes of fatty deposits, the composition that perhaps contains it gives individual step.
In one embodiment, SARM compound of the present invention is used for: a) treatment, prevention, compacting, inhibition or minimizing atherosclerosis; B) treatment, prevention, compacting, inhibition are because the hepatic injury that fatty deposits causes.
In one embodiment, refer to can be from innermost layer chronic, the complex disease that begin of infringement artery for atherosclerosis.In another embodiment, the reason of infringement arterial wall can comprise that a) the Blood Cholesterol level raises; B) hypertension; C) smoke of tobacco; D) diabetes.In another embodiment, be true although smoke of tobacco may make atherosclerosis more worsen and accelerate that it grows in coronary artery, Aorta and leg arteries, this illness is medicable in the smoker.Similarly, in another embodiment, method of the present invention can be used for treating the individuality with the vascular disease family medical history of making up one's mind the morning that increases Atherosclerosis Risk.
In one embodiment, because the hepatic injury that causes of fatty deposits refers to increasing of in the liver cell that forms fatty liver fat, wherein said fatty liver may or cause the inflammation of liver with the inflammation-related of liver.This can cause scar and the sclerosis of liver.When scar becomes extensive, be called cirrhosis.In another embodiment, fat accumulation becomes obesity in liver.In another embodiment, fatty liver is also relevant with excessive use alcohol with diabetes, hypertriglyceridemia.In another embodiment, fatty liver can with vitamin A excessive in some disease such as pulmonary tuberculosis and malnutritive, fat intestines by-pass operation, the body or use some drugs such as valproic acid (trade(brand)name: Depakene/Depakote) and reflunomide (cortisone, prednisone) occur.Sometimes fatty liver occurs as pregnancy complications.
In one embodiment, be used for the treatment of in the individual method, described individuality is the people, and in another embodiment, described individuality is the male sex, and perhaps in another embodiment, described individuality is the women.
In another embodiment, the composition that the invention provides SARM of the present invention or contain it promote or the spermatogeny of compacting male individual in application.SARM more of the present invention show short male active in addition, therefore stimulate spermatogeny.In another embodiment, SARM of the present invention shows antagonistic activity in the sexual gland of individuality, therefore can suppress spermatogeny.In one embodiment, therefore described SARM can be used as contraceptive bian.
Should understand, any application of SARM of the present invention, comprise also being a part of the present invention about the application in the application of the disease relevant with muscle, fat, heart, liver, sexual gland or osseous tissue or illness particularly, wherein SARM compound of the present invention or contain the course of disease that gives advantageously to change these diseases or illness of its composition.
Provide following embodiment with illustration the preferred embodiments of the invention more fully.Yet, never they should be interpreted as to limit wide protection domain of the present invention.
Embodiment
Embodiment 1:
SARM (SARM) compound III is divided into scleroblast and broken to progenitor cell The effect of osteocyte
Materials and methods
Pharmaceutical chemicals
Compound III, THT and PTH are with the concentration preparation of 1nM-1 μ M.
Animal
The peaceful and comfortable execution of female rats in age in April is with the animal distal femoral resection.Remove any muscle and reticular tissue on the femur, and in the minimum essential medium that contains penicillin, Streptomycin sulphate and amphotericin B (MEM) in storing until cell cultures on ice.
Medullary cell is cultivated
All cell culture materials are all available from Invitrogen (Carlsbad, CA).At first femur is cleaned in 70% ethanol, and wash three times with penicillin and each 5ml of Streptomycin sulphate.The femur two ends are all fractureed, and medullary cell washes in the 50ml tapered tube with the MEM that 15ml contains penicillin, Streptomycin sulphate and amphotericin B, and is storing on ice.All femurs are carried out same step.Medullary cell is mixed, and in clinical centrifuge with 1000rpm centrifugal 5 minutes.Cell is resuspended among the MEM of the serum, penicillin, Streptomycin sulphate and the amphotericin B that do not contain phenol red and additional 10% active carbon desorption.Cell is passed through the 22g pin to grind, the microscopically counting, be seeded in every hole 1,500,000 cells among the MEM of the serum that does not contain phenol red and additional 15% active carbon desorption, penicillin, Streptomycin sulphate, 300ng/ml amphotericin B, 0.28mM xitix and 10mM β-Phosphoric acid glycerol esters in 6 orifice plates, to break up to inoblast/scleroblast system, and be seeded in every hole 2,500,000 cells among the MEM of amphotericin B of the serum that does not contain phenol red and additional 10% active carbon desorption, penicillin, Streptomycin sulphate and 300ng/ml in 24 orifice plates, with to the differentiation of osteoclast system.Replaced medium on the 2nd, and use described HORMONE TREATMENT.Osteoclast culture carries out inducing osteoclast to generate in the presence of 50ng RANK part and 10ng GM-CSF.For Osteoclast culture, the complete replaced medium every three days.Cultivate for scleroblast, changed half substratum every three days to stay the somatomedin of emiocytosis.
Cell dyeing
When 12 end of day,, and for the Osteoclast culture thing cell is fixed in 4% formaldehyde in cell stuck-at-1 0% buffered formalin for fibroblast cell cultures.Inoblast is used for alkaline phosphatase activities dyeing, uses as mentioned previously spectrophotometer to measure O.D. under 405nm.Osteoclast is used for Tartrate resistant acid phosphatase active (TRAP) dyeing, has the cell of 2 or more nuclears and as mentioned previously mapping at the microscopically counting.
The result
SARM is that medullary cell is to the strong inductor of scleroblast and the differentiation of osteoclast system
Male sex hormone has anabolic action to bone, for example lacks male sex hormone among the androgen-deprivation of prostate cancer treatment and the elderly in some cases and has clearly illustrated that male sex hormone is as the benefit of bone protection hormone.Yet the androgenic use of dystopy is restricted owing to its side effect and owing to male sex hormone is converted into estrogenic risk.
In order to determine whether SARM can have therapeutic action and avoid above-mentioned side effect; have the ability of bone provide protection and side effect aspect still less (seen such as female hormone) with regard to SARM (SARM), various SARM are estimated.Make the 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, effectiveness and the SARM compound III of dihydrotestosterone (DHT) and parathyroid hormone (PTH) compared (Fig. 1 and 2).The above hormone exist or not in the presence of rat bone marrow cell was cultivated in substratum 12, and be that the differentiation aspect is estimated with regard to them to scleroblast and osteoclast.
DHT and compound III all increase former generation medullary cell to the differentiation of scleroblast system, shown in alkaline phosphatase (ALP) activity measurement of cell (Fig. 1).Under 1 μ M concentration, the ALP that DHT and SARM induction phase are worked as is active, and under low concentration 100nM and 10nM, compound III shows to have larger inducing than DHT, PTH, and another bone anabolic hormone is only under higher concentration and do not induce ALP dyeing under low concentration.
Fig. 2 shows when cell is cultivated in the presence of RANK part and GM-CSF, the obvious increase of the quantity of the positive multinucleated osteoclast of TRAP.The cell of processing with DHT or SARM significantly suppresses the positive multinucleated osteoclast propagation of TRAP that RANK part and GM-CSF induce.PTH suppresses to induce under higher concentration, yet under low concentration, PTH has but increased the quantity of the positive osteoclast of TRAP.Under the dosage of all evaluations, estradiol all suppresses osteoclast and generates.
Embodiment 2:
SARM separately and with the bone effect of anti-again absorption agent Alendronate associating
Materials and methods
60 female, unpregnancies, complete 23 age in week the Sprague-Dawley rat obtain from Charles RiverLaboratories (Wilmington, MA).Every cage is raised 2-3 animal, and adapts to 12-h illumination/dark cycle.Freely obtain food (7012C LM-485 mouse/rat sterilization diet, HarlanTeklad, Madison, WI) and water.The animal agreement of the research obtains Institutional Animal Care and Use Committee examination and the approval of the state university of Tennessee.
Sham-operation or ovariectomy were carried out on 0th.This research is comprised of six following 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 began every Nikkei tube feed on 1st and gives dosage (200L).Execution animal on the 45th in this research.Take out femur, remove soft tissue, and in SS saline soaked gauze, under-20 ℃, store until analyze.9 animal deads are arranged during studying.Complication and the technology mistake in oral administration (namely being delivered in the lung to drug solns) that these death cause owing to ovariectomy.The dosage group is listed in table 1.
Figure BDA00002515436200351
Table 1, treatment group
Fl is sent to SkeleTech Inc. (Bothell, WA) is used for biomechanical strength (three-point bending method) and pQCT analysis.Stratec XCT RM and related software (Stratec MedizintechnikGmbH, Pforzheim, Germany.Software version 5.40C) are used for pQCT and analyze.All analyze in femur stage casing and remote area.Middle piecewise analysis is carried out in the zone at 50% place of femur length.The far-end analysis is carried out in 20% zone of the femur length that begins from distal tip.Use is used for analyzing perpendicular to the thin slice of the 0.5mm of femur major axis.Total bone mineral content, long-pending, the total bone mineral density of total surface of bone, cortex bone mineral content, cortex bone area, cortex bone mineral density, cortical thickness, periosteum girth (circumferentia) and perimyelis girth are measured in the femur stage casing.Measure total bone mineral content, long-pending, the total bone mineral density of total surface of bone, trabecular bone mineral content, trabecular bone area and trabecular bone mineral density in distal femur.After pQCT analyzed, femoral strength was measured by three-point bending.Measure radius vector (the APD) (unit: mm) of femur stage casing mid point with electronic caliper.Femur is placed on the pillar of three-point bending device below of Instron Mechanical Testing Machine (it is 5500 that Instron 4465 has renovated) (Canton, MA), face down before making femur.The length (L) of a below intercolumniation is set as 14mm.Make the center in the device aligning femur stage casing of top load.Use constant displacement speed 6mm/min until femur fractures.The mechanical test instrument is directly measured overall loading (F u) (unit: N), stiffness (S) (unit: N/mm) can (W) (unit: mJ) with absorption.Axial area moment of inertia (I) (unit: mm 4) calculate by the software in the femur stage casing pQCT analysis.Stress (σ) (unit: N/mm 2), Young's modulus (E) (unit: Mpa) and intensity (T) (unit: mJ/m 3) calculate 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 check and carries out.Think that the P-value is less than statistically-significant difference was arranged at 0.05 o'clock.
The result:
The femur overall loading is measured by the 3-point bending method of femur.The result is presented among Fig. 3.Between complete vector (210N) control group and OVX carrier (212N) control group, do not observe difference.We observe the compound III treatment group and compare with close set and OVX group respectively and have the trend that overall loading increases to 224 and 233 newton.Alendronate (213N) is compared with control group with Alendronate+compound III (207N) group does not have difference.
Analyze the trabecular bone mineral density of distal femoral by pQCT.The result is presented among Fig. 4.Significant trabecular bone lost after we observed OVX.In complete vector control group and OVX vehicle Control group, trabecular bone density is down to 215mg/cm from 379 respectively 3In the intact animal of processing with compound III, we observe slight the increasing of trabecular bone density and reach 398mg/cm 3In the OVX animal of processing with compound III, we observe with respect to OVX vehicle Control group and significantly increase to 406mg/cm 3The trabecular bone density that Alendronate is processed increases to 480mg/cm 3The combination therapy of Alendronate and compound III shows addition effectiveness, makes trabecular bone density increase to 552mg/cm 3
Embodiment 3:
Short hero Huo Xing ﹠amp in complete sum ORX rat; Anabolic activity
Materials and methods
The male Spargue-Dawley rat of heavily about 200g is available from Harlan Bioproducts forScience (Indianapolis, IN).Animal is kept 12 hours illumination/dark cycles, and can freely obtain food (7012C LM-485 mouse/rat sterilization diet, Harlan Teklad, Madison, WI) and water.The animal agreement obtains Institutional Animal Care and UseCommittee examination and the approval of the state university of Tennessee.The anabolism of assessing compound III in intact animal and short male active also estimated the dose response in acute testectomy (ORX) animal in addition.Also estimated the regeneration of compound III in chronic (9 days) ORX rat.
Described compound weighed and be dissolved among the DMSO (Fisher) of 10% usefulness PEG 300 (Acros Organics, NJ) dilution, for the preparation of suitable dose concentration.Raise 2-3 animal in each cage.The random assignment of complete sum ORX animal is become 7 groups, and every group is comprised of 4-5 animal.Control group (complete sum ORX) gives carrier every day.I through tube feed with compound III with dosage 0.01,0.03,0.1,0.3,0.75 and give complete sum ORX group 1mg/ day.
Neuter (first day of this research) is divided into 0.01,0.03,0.1,0.3,0.75 and 1mg/ per daily dose group (4-5 animal/group) at random, is used for the dose response evaluation.Beginning administration on the 9th behind the ORX was through tube feed administration every day 14 days.(ketamine/dimelazine (xyalzine) 87:13mg/kg) is put to death, and the record body weight with Animal Anesthesia after the dosage regimens on the 14.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 complete control group.Use more independent dosage group and the complete control group of Student ' s T check.P value<0.05 priori is defined as significantly.As short male active measuring, row gland siphonal lobe and seminal vesicle weight are estimated, and musculus levator ani weight is as estimating anabolic measuring.Collect blood from aorta abdominalis, centrifugal, before measuring hormone serum level that serum is frozen under-80 ℃.Serum lutropin (LH) and follicle stimulating hormone (FSH) concentration are measured by the Center for Research in Reproduction Ligand Assayand Analysis Core of Fu Jiliya university (NICHD (SCCPRR) Grant U54-HD28934).
The result:
Give dosage 0.01,0.03,0.1,0.3,0.75 and 1mg/ after day, the weight of prostate after compound III is processed is respectively 111% ± 21%, 88% ± 15%, 77% ± 17%, 71% ± 16%, 71% ± 10% and 87% ± 13% (Fig. 5) of complete control group.Similarly, give dosage 0.01,0.03,0.1,0.3,0.75 and 1mg/ after day, seminal vesicle weight is reduced to respectively 94% ± 9%, 77% ± 11%, 80% ± 9%, 73% ± 12%, 77% ± 10% and 88% ± 14% of complete control group.But in all dosage groups when comparing with complete contrast, the musculus levator ani weight of observing the sham-operation animal significantly increases.Corresponding to 0.01,0.03,0.1,0.3,0.75 and 1mg/ per daily dose group, musculus levator ani weight is respectively 120% ± 12%, 116% ± 7%, 128% ± 7%, 134% ± 7%, 125% ± 9% and 146% ± 17% of complete contrast.The result provides with chart in Fig. 5.
Compound III partly keeps weight of prostate behind the male castration.Weight of prostate is down to 5% ± 1% of complete contrast in the ORX of vehicle treated contrast.Be 0.01,0.03,0.1,0.3,0.75 and 1.0mg/ during day at dosage, it is 8% ± 2%, 20% ± 5%, 51% ± 19%, 56% ± 9%, 80% ± 28% and 74% ± 12.5% of complete contrast that compound III keeps respectively weight of prostate.In the castrating contrast, seminal vesicle weight is down to 13% ± 2% of complete control group.Compound III partly keeps seminal vesicle weight in the ORX animal.Give 0.01,0.03,0.1,0.3,0.75 and the 1.0mg/ per daily dose after, the seminal vesicle weight of the animal of drug treating is respectively 12% ± 4%, 17% ± 5%, 35% ± 10%, 61% ± 15%, 70% ± 14% and 80% ± 6% of complete contrast.In the ORX contrast, musculus levator ani weight is down to 55% ± 7% of complete control group.In the musculus levator ani of the animal that compound III is processed, we observe anabolic action.Compound III is at dosage〉0.1mg/ keeps musculus levator ani weight fully during day.With comparing of in complete contrast, observing, dosage〉cause musculus levator ani weight significantly to increase 0.1mg/ day.For 0.01,0.03,0.1,0.3,0.75 and 1.0mg/ per daily dose group, in the per-cent of complete control group, musculus levator ani weight is 59% ± 6%, 85% ± 9%, 112% ± 10%, 122% ± 16%, 127% ± 12% and 129.66% ± 2%.The result provides with chart in Fig. 6.E at each tissue MaxAnd ED 50Value is passed through
Figure BDA00002515436200381
In nonlinear regression analysis determine, and in Fig. 7, provide.The E of prostate gland, seminal vesicle and musculus levator ani MaxValue is respectively 83% ± 25%, 85% ± 11% and 131% ± 2%.The ED of prostate gland, seminal vesicle and musculus levator ani 50Respectively 0.09 ± 0.07,0.17 ± 0.05 and 0.02 ± 0.01mg/ day.
Serum hormone is analyzed
The serum Lh of animal and FSH data provide in table 1.LH all reduces in the dose-dependently mode in the complete sum neuter.Giving dosage〉0.1mg/ is after day, and the LH level is lower than quantitative limit (0.07mg/ day).The 0.1mg/ per daily dose makes the LH level get back to level seen in the complete control group in the ORX animal.Also observe similar effect for FSH.In intact animal, 0.75 and the 1mg/ per daily dose observe the FSH level and significantly reduce.In the ORX animal, observe the horizontal dose-dependently of FSH and reduce.In the ORX animal, the dosage of compound III〉make the FSH level get back to complete control level 0.1mg/ day.
Serum Lh and the FSH level of table 1.Arm1 and Arm2 animal. aThe complete contrast of P<0.05vs.. bP<0.05vs.ORX contrast.
Short hero Huo Xing ﹠amp after the delay administration; Anabolic activity
In the ORX animal, compound III is partly recovered prostate gland and seminal vesicle weight.For 0.01,0.03,0.1,0.3,0.75 and 1.0mg/ per daily dose group, prostate gland returns to respectively 9% ± 3%, 11% ± 3%, 23% ± 5%, 50% ± 13%, 62% ± 12% and 71% ± 5% of complete contrast, and seminal vesicle regain one's integrity the contrast 7% ± 1%, 9% ± 1%, 23% ± 8%, 49% ± 5%, 67% ± 12% and 67% ± 11%.Compound III is at dosage〉0.1mg/ is during day, recovers musculus levator ani weight fully.Corresponding to dosage 0.01,0.03,0.1,0.3,0.75 and 1.0mg/ day, musculus levator ani weight returns to respectively 56% ± 7%, 82% ± 9%, 103% ± 11%, 113% ± 11%, 121% ± 7% and 120% ± 7%.The result provides with chart in Fig. 8.The E of each tissue MaxAnd ED 50Value is passed through In nonlinear regression analysis determine, and in Fig. 9, provide.The E of prostate gland, seminal vesicle and musculus levator ani MaxValue is respectively 75% ± 8%, 73% ± 3% and 126% ± 4%.The ED of prostate gland, seminal vesicle and musculus levator ani 50Respectively 0.22 ± 0.05,0.21 ± 0.02 and 0.013 ± 0.01mg/ day.
Embodiment 4:
The Pharmacokinetic Characteristics of new oral anabolism SARM compound III:
First analysis in the healthy male volunteers
Materials and methods
With the randomized, double-blind research and design maximum one group of 12 healthy male volunteers is carried out administration with each dosage level (9 activity, 3 placebos).Recruit 8 groups (age 18-45 years), once single oral dosage is received in every winding, and described dosage is corresponding to 1,3,10,30 and 100mg compound III in solution (or isopyknic PEG 300 placebos) or 3 or 30mg compound III in the test capsule.Studied the impact of micronization (being that particle diameter reduces) on the pharmacokinetics of compound III with the form of 30mg solid oral dosage form.The sample that is used for female medicine Pharmacokinetic Evaluation is collected after administration and is reached 72 hours.
The result
Dosage be 1,3,10,30 and the compound III in the PEG300 based sols of 100mg fast from gastrointestinal absorption.All dosage waters on average cause to the last all gageable compound III plasma concentrations (Figure 10-12) of a collection time point (72 hours).Contact (the C of compound III MaxAnd AUC) increase with dosage, and linear in dosage 1-100mg scope for solution.For the compound III in solution, (intermediate value=1.0 hour) obtain T between 0.8 and 2.3 hour Max, and give between 3.2 and 3.9 hours, to obtain T behind the solid orally ingestible Max(Figure 13 and 14).For 1-100mg solution and 3mg capsule, eventually to eliminate the transformation period be 19 to 22 hours (intermediate value=20 hour) at the end, for 30mg micronization and non-micronization capsule, increases to 27 and 30 hours, but do not have significance (p〉0.1).Oral clearance is oppositely relevant with the transformation period, compares with dosage with other formulation, and the non-micronization capsule of 30mg shows the long half-lift and the minimum clearing rate.The non-micronization capsule of 3mg and solution have equal bioavailability, but improve oral administration biaavailability (p<0.5) (Figure 12) in higher dosage (30mg) micronization.As indicated in the second continuous peak in eliminating mutually such as medicine, it is possible playing an important role in the redistributing of female medicine through the enterohepatic circulation of liver and gall.
Embodiment 5
The anabolism of SARM and short male active
Material: according to the synthetic SARM of the method for describing among the U.S. Patent Application Publication 2004/0014975A1.Alzet osmotic pump (2002 type) is available from Alza Corp. (Palo Alto, CA).
The SARM of test will comprise as follows:
Figure BDA00002515436200411
With
The specific activity of their activity and following compound is:
Figure BDA00002515436200413
Research and design: with the Sprague-Dawley rat random packet of immature heavy 90-100mg, every group of at least 5 animals.In before the drug treating one day of beginning, from cage, take out animal is single, weigh and give ketamine/dimelazine (87/13mg/kg by intraperitoneal; About 1mL/kg) anesthesia.When suitable anesthesia (namely to pinching not reaction of toe), for the purpose confirmed gives mark with the ear of animal.Then animal is placed on the sterile pad, cleans its belly and scrotum with povidone iodine and 70% ethanol.Cut the taking-up testis via middle line of scrotum, aseptic suture is used for ligation testis top tissue, then each testis of surgical removal.Close the wound position with aseptic stainless steel wound clips, and clean this position with povidone iodine.Allow animal revive at sterile pad (until can stand), then they are put back in the cage.
After 20 hours, with ketamine/dimelazine animal is anaesthetized again, and the Alzet osmotic pump (2002 type) that will contain the SARM compound through subcutaneous placement in the omoplate district.Osmotic pump contains the suitable medicine (as described in Example 3) that is dissolved in the Liquid Macrogol (PEG 300).Fill osmotic pump at the implantation proxima luce (prox. luc) with suitable solution.Every day monitor animal to the acute toxic symptoms of drug treating (as drowsiness, fur is coarse).
After the drug treating 14 days, with ketamine/dimelazine anesthetized animal.By sacrificed by exsanguination animal under anesthesia.Collect blood sample by the aorta abdominalis venipuncture, and carry out the whole blood cell analysis.A part of blood sample is placed in the separator tube with 12000g centrifugal 1 minute.Remove plasma layer and lower frozen at-20 ℃.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 that contains 10% neutral buffered formalin.Anticorrosion tissue is used for histopathological analysis.
Be data analysis, the weight of all organs is carried out stdn with body weight, carries out the statistical significant difference analysis by single factor ANOVA.The weight of prostate gland and seminal vesicle is as the index of estimating short male activity, and musculus levator ani weight is used for estimating anabolic activity.
Be used as the positive controls of anabolism and short male effect with the testosterone propionate (TP) that increases dosage.Thereby effect and the TP of specific compound can be compared.
The weight that is expected at prostate gland, seminal vesicle and musculus levator ani in the rat of castrating, vehicle treated significantly reduces because of the cut-out that the endogenous male sex hormone produces.The external source of expection testosterone propionate, short hero and anabolic steroid gives and will increase the weight of castrating rat prostate, seminal vesicle and musculus levator ani in the dose-dependently mode.The impact of SARM on the weight of neuter prostate gland, seminal vesicle and musculus levator ani will be estimated comparatively.Aspect the weight that increases prostate gland and seminal vesicle, show low usefulness and intrinsic activity, and increasing the compound that shows higher performance and intrinsic activity aspect the weight of musculus levator ani, to be considered to short male a little less than, but have anabolic activity, representative will be used for the treatment of prostate cancer for example or be used for the treatment of the compound that relevant side effect is treated in and at present treatment of prostate cancer as androgen-deprivation.
Embodiment 6
SARM is to the reduction of the level of cholesterol
Materials and methods
100 Spargue Dawley rats (50 male and 50 female) are divided into 5 groups (every group every kind sex n=10), and its representative only has carrier (PEG 300:40%
Figure BDA00002515436200431
[75/25 (v/v)]) group and four dosage groups of compound III.With animal according to their nearest body weight with 0,3,10,30 or the dosage of 100mg/kg give once a day compound III by tube feed.During studying, rat is drinking-water and Harlan Taklad Rodent Chow standard laboratory diet arbitrarily.Behind the successive administration 28 days, with the animal overnight fasting, collect blood sample, and process to obtain serum.Use automatic laboratory determination method to measure serum total cholesterol level.
The result
Male and serum cholesterol value female rats in only having vehicle group (0mg/kg) is respectively 92 ± 13.5 and 102 ± 13mg/L.Think that these values are in the normal historical range of test laboratory.Oral dosage every day of compound III is 3mg/kg or causes that all total cholesterol level significantly reduces when higher in male and female rats.When 3mg/kg, compare with the vehicle Control animal, it is about 30% to notice that total cholesterol reduces, wherein male and femalely be respectively 63 ± 17.4 and 74 ± 14.2mg/L.Although noticing in maximum dose level group (100mg/kg/ day) has slight larger effect, in general, dose-response relationship is not observed in the minimizing about total cholesterol level in Spargue Dawley rat.This result provides with diagrammatic form in Figure 15.
To estimate the effect of SARM in causing acute toxicity, and test and dock subject animal visual inspection by the diagnosis hematology and measure, with compacting lutropin (LH) or follicle stimulating hormone (FSH) described in above embodiment 4.
Although this paper is illustration and described some feature of the present invention, many modifications will occur, substitute, change and be equal to alternative to those skilled in the art.It is therefore to be understood that appended claim is intended to contain all and falls into the interior modifications and variations of connotation of the present invention.

Claims (30)

1. SARM (SARM) compound or its isomer, pharmacologically acceptable salts or its arbitrary combination by the representative of the structure of formula (III):
Figure FDA00002515436100011
2. composition, it contains the SARM compound of claim 1 and suitable carrier or thinner.
3. the composition of claim 2, it also contains Alendronate.
4. the SARM compound of claim 1 or the composition that contains it suffer from application in the bone photo related disorders individuality in treatment.
5. the application of claim 4, wherein said bone photo related disorders are osteoporosis, osteopenia, bone resorption increase, fracture, bone fragility, bone mineral density (BMD) reduction or its arbitrary combination.
6. the application of claim 4, wherein said composition also contains Alendronate.
7. the SARM compound of claim 1 or the composition that contains it are increasing individual bone strength or bone amount or are promoting application in the individual bone forming.
8. the application of claim 7, wherein said composition also contains Alendronate.
9. the application of claim 7, wherein said bone is cortex bone.
10. the application of claim 7, wherein said bone are trabecular bone or spongy bone.
11. stimulating or be enhanced to osteocyte, the application of claim 7, wherein said SARM compound generate.
12. the application of claim 7, wherein said SARM compound suppress osteoclast propagation.
13. suffering from muscle, the application of claim 7, wherein said individuality reduce disease or emaciation.
14. the SARM compound of claim 1 or contain its application of composition in intervention or preventing osteoporosis or osteopenia.
15. the application of claim 9, wherein said individuality suffers from osteoporosis.
16. the application of claim 9, wherein said osteoporosis are that hormone causes.
17. the SARM compound of claim 1 or the composition that contains it in treatment, prevention, compacting, suppress individual wasting disease or reduce application in the incidence of individual wasting disease.
18. the application of claim 17, wherein said wasting disease is caused by pathology, slight illness, disease or illness.
19. the application of claim 18, wherein said pathology, slight illness, disease or illness are nervosa, infectivity, chronic or genetic.
20. the application of claim 19, wherein said pathology, slight illness, disease or illness are muscular dystrophy, myatrophy, the chain ridge bulbar muscular atrophy of X (SBMA), emaciation, malnutrition, leprosy, diabetes, ephrosis, chronic obstructive pulmonary disease (COPD), cancer, renal failure in latter stage, muscle minimizing disease, pulmonary emphysema, osteomalacia, HIV infection, AIDS, congestive heart failure (CHF) or myocardosis.
21. the application of claim 17, wherein said wasting disease are relevant wasting diseases of age; The useless wasting disease of degenerating and being correlated with sexual function; Or described wasting disease is by chronic back pain; Burn; Central nervous system (CNS) damage or infringement; Peripheral nerve injury or infringement; Spinal injury or infringement; Chemical damage or infringement; Perhaps alcoholism causes.
22. the application of claim 17, wherein said composition gives through intravenously, intra-arterial or intramuscular with liquid form; Be implanted subcutaneously in the described individuality with the piller form; Give so that the liquid or solid form is oral; Give with liquid or solid form hypogloeeis; Perhaps described pharmaceutical composition is locally applied to the mucomembranous surface of described individuality.
23. the application of claim 19, wherein said composition are pill, tablet, capsule, solution, suspensoid, emulsion, elixir, gelifying agent, emulsifiable paste, suppository or parenteral administration.
24. the SARM compound of claim 1 or the application of composition in increasing individual muscle behavior performance, muscle size, muscular strength or its arbitrary combination that contains it.
25. the SARM compound of claim 1 or the composition that contains it are in the relevant obesity of the individual metabolism syndrome for the treatment of or the application in the diabetes.
26. the application of claim 25, wherein said individuality suffers from hormone imbalances, disorder or disease.
27. the application of claim 26, wherein said individuality is in climacteric.
28. the application of claim 26, wherein said SARM increases the thin heavy of individuality.
The application during 29. the SARM compound of claim 1 or the composition that contains it recover after promoting or accelerating operation technique.
30. the SARM compound of claim 1 or the composition that contains it promote or the spermatogeny of compacting male individual in application.
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US10/861,923 US8008348B2 (en) 2001-12-06 2004-06-07 Treating muscle wasting with selective androgen receptor modulators
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US10/863,524 2004-06-09
US10/863,524 US20050038110A1 (en) 2000-08-24 2004-06-09 Selective androgen receptor modulators and methods of use thereof
US10/961,380 2004-10-12
US10/961,380 US20060019931A1 (en) 2003-10-14 2004-10-12 Treating bone-related disorders with selective androgen receptor modulators
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