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CN1964712A - Selective androgen receptor modulators and methods of use thereof - Google Patents

Selective androgen receptor modulators and methods of use thereof Download PDF

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CN1964712A
CN1964712A CN 200580018468 CN200580018468A CN1964712A CN 1964712 A CN1964712 A CN 1964712A CN 200580018468 CN200580018468 CN 200580018468 CN 200580018468 A CN200580018468 A CN 200580018468A CN 1964712 A CN1964712 A CN 1964712A
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sarm
another embodiment
bone
sarm compound
individual
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詹姆斯·T.·多尔顿
杜安·D.·米勒
卡伦·A.·韦韦尔卡
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University of Tennessee Research Foundation
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University of Tennessee Research Foundation
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Abstract

本发明提供SARM化合物及其在治疗个体中多种疾病或病症中的应用，所述疾病或病症特别是包括肌肉消瘦疾病或病症或者骨相关疾病或病症。The present invention provides SARM compounds and their use in the treatment of various diseases or conditions in an individual, including, inter alia, muscle-wasting diseases or conditions or bone-related diseases or conditions.

Description

SARM and using method thereof
Background technology
Androgen receptor (" AR ") is the activated NlmR of part, and it is induced by its endogenous androgenic activity mediation male's sexual development and function.Androgen is commonly called male sex hormone.Androgen is to be produced in vivo by testis and adrenal cortex, perhaps can be in laboratory synthetic steroid.Androgenic steroids plays an important role in many physiological process, comprise the growth of male sex characteristics such as muscle and bone amount and keep, prostate growth, spermatogenesis and male's hair distribute (Matsumoto, Endocnnol.Met.Clin.N.Am.23:857-75 (1994)).Endogenous steroid androgen comprises testosterone and dihydrotestosterone (" DHT ").Testosterone is the main steroid by testicular secretion, and is the main circulation androgen of finding in male's serum.In many peripheral tissues, testosterone is changed into DHT by the enzyme 5.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 androgen comprises the ester of testosterone, as cipionate, propionic ester, phenylpropionic acid ester, cyclopentanepropanoiacid acid ester, isocarporate, heptanoate and decanoin, and other synthetic androgen, as 7-methylnortestosterone (" MENT ") and acetas (people such as Sundaram thereof, " 7 Alpha-Methyl-Nortestosterone (MENT): The Optimal Androgen For Male Contraception; " Ann.Med, 25:199-205 (1993) (" Sundaram ")).Because AR participates in male's sexual development 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 disease, 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 the individual death of 5-20%, the survivor maimed person more than 50% every year.The old people suffers from osteoporotic risk maximum, therefore estimates along with this problem of aged tendency of 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.Women's internal skeleton loss in 5 years after menopause is obviously quickened.Other factor that increases this risk comprises smoking, alcohol abuse, sedentary lifestyle and the absorption of low calcium.Yet osteoporosis also often takes place in the male.Determine that clearly male'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 gonadal hormone pleiotropic effects in non-germinal tissue has just begun to be familiar with, but androgen and estrogenic physiological concentration are clearly to keeping the bone stable state to play an important role in whole life.Therefore, when androgen or estrogen forfeiture generation, consequently bone remodeling speed increases, and the balance that absorbs and form is tilted for helping absorption, and this causes whole bone amount loss.In the male, the minimizing (androgenic direct minimizing and the lower estrogen level derived from androgenic periphery aromatisation) naturally of maturity hormone is relevant with bone fragility.This effect is also observed in the castrating male.
Wasting disease refers to muscle quantities progressive loss and/or muscle, comprises skeletal muscle or voluntary muscle, the cardiac muscle (cardiomyopathy) of control heart and the gradual unable and degeneration of smooth muscle of controlled motion.Chronic wasting disease is chronic disease (promptly continuing segment length's time), it is characterized in that the progressive loss of muscle quantities, the unable and degeneration of muscle.
The feature of the muscle quantities loss that takes place during wasting disease can be that myogen 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 takes place.The myogen degraded no matter be to be caused or caused by the synthetic degree of low-protein by the high protein degree of degradation, all cause the muscle quantities minimizing and causes wasting disease.
Wasting disease is relevant with chronic, nerve, heritability or infectiousness pathology, disease, slight illness or disease.These comprise muscular dystrophy, as bulbar paralysis muscular dystrophy and myotonia atrophica; Amyotrophy is as amyotrophy after the poliomyelitis (PPMA); Cachexia reduces disease (sarcopenia), emphysema, osteomalacia, HIV infection, AIDS and cardiomyopathy as heart cachexia, AIDS cachexia and cancer cachexia, malnutrition, leprosy, diabetes, nephropathy, chronic resistive pneumonopathy (COPD), cancer, renal failure in latter stage, muscle.
In addition, other environment is relevant with wasting disease with disease, and can cause wasting disease.These comprise chronic back pain, advanced age, central nervous system (CNS) damage, peripheral nerve injury, spinal cord injury, chemical damage, central nervous system (CNS) infringement, peripheral lesion, spinal cord lesion, chemical damage, burn, because ailing or damage causes that extremity fix, take place when being in hospital for a long time uselessly degenerates (disuse deconditioning) with sexual function, 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 myogen synthetic.
If the unabated words of wasting disease have fearful health consequences.For example, the variation that takes place during wasting disease may cause health 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 a strong precursor of suffering from cachexia 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) chemical compound or its prodrug, analog, isomer, metabolite, derivant, the acceptable salt of pharmacy, medicine, polymorph, crystal, impurity, N-oxide, hydrate or its combination in any of representing by the structure of formula (I):
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) chemical compound or its prodrug, analog, isomer, metabolite, derivant, the acceptable salt of pharmacy, medicine, polymorph, crystal, impurity, N-oxide, hydrate or its combination in any of representing by the structure of formula (III):
Figure A20058001846800112
In another embodiment, the invention provides SARM (SARM) chemical compound or its prodrug, analog, isomer, metabolite, derivant, the acceptable salt of pharmacy, medicine, polymorph, crystal, impurity, N-oxide, hydrate or its combination in any of representing by 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:
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 para-position, and perhaps in another embodiment, Y is in a position, perhaps in another embodiment, and their combination in any.
In another embodiment, the invention provides a kind of pharmaceutical composition, it contains formula (I), (III) or SARM chemical compound (IV) and suitable carriers or diluent.
In another embodiment, the compositions that the invention provides formula (I), (III) or chemical compound (IV) or contain it suffers from application in the individuality of bone photo related disorders in treatment.
In another embodiment, the compositions that the invention provides formula (I), (III) or chemical compound (IV) or contain it is increasing individual bone strength or bone amount or is promoting application in the individual bone formation.
In another embodiment, the invention provides formula (I), (III) or chemical compound (IV) is used for the treatment of, prevents, suppresses, suppresses individual wasting disease or reduce application in the incidence rate of individual wasting disease.
In another embodiment, the invention provides formula (I), (III) or chemical compound (IV) in the application that increases individual muscle behavior performance, muscle size, muscular strength or its combination in any.
In another embodiment, the compositions that the invention provides formula (I), (III) or chemical compound (IV) or contain it is in relevant obesity of the individual metabolism syndrome of treatment or the application in the diabetes.
In another embodiment, the application during the compositions that the invention provides formula (I), (III) or chemical compound (IV) or contain it is recovered after promoting or quickening operation technique.
In another embodiment, the compositions that the invention provides formula (I), (III) or chemical compound (IV) or contain it promote or the spermatogenesis of compacting male individual in application.
The accompanying drawing summary
Fig. 1: SARM, DHT and PTH are to the effect of rat bone marrow cell to the differentiation of osteoblast system.
Fig. 2: SARM, DHT and PTH are to the effect of the positive multinucleated osteoclast of TRAP.
Fig. 3: the femur maximum load that 3 bending methods of femur are measured.
Fig. 4: the trabecular bone mineral density of the distal femoral of pQCT assay determination.
Fig. 5: the pharmacology of compound III in complete rat.
Fig. 6: the organ weight of the castrating rat that compound III is handled, represent with the percentage ratio of complete contrast. *The complete contrast of P value＜0.05vs..
Fig. 7: the organ weight of compound III keeps dose-response curve in the castrating rat.The E of levator ani m. (closed triangle), prostate (open loop) and seminal vesicle (closed square) MaxAnd ED 50Value is by using the sigmoid curve E among the WinNonlin  MaxModel carries out nonlinear regression analysis and obtains.
Fig. 8: the organ weight of the castrating rat that compound III is handled, represent with complete percentage ratio 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 levator ani m. (closed triangle), prostate (open loop) and seminal vesicle (closed square) MaxAnd ED 50Value is by using the sigmoid curve E among the WinNonlin  MaxModel carries out nonlinear regression analysis and obtains.
Figure 10: the serum-concentration-time plot of the compound III of orally give 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 administration solution (G100401) 0-inf
Figure 14: the dosage vs.C of oral administration solution Max
Figure 15: the cholesterol of compound III reduces in the rat.
The specific embodiment
In the following specific 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, known method, step and component are not described in detail in order not make the present invention.
In one embodiment, the invention provides a kind of SARM (SARM) chemical compound or its prodrug, analog, isomer, metabolite, derivant, the acceptable salt of pharmacy, medicine, polymorph, crystal, impurity, N-oxide, hydrate or its combination in any of representing by the structure of formula (I):
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 the SARM that represents by the structure of formula (II):
Wherein X is O;
Z is NO 2, CN, COR or CONHR;
Y is I, CF 3, Br, Cl, F or Sn (R) 3
R is alkyl or OH; And
Q is CN.
In one embodiment, the invention provides SARM (SARM) chemical compound or its prodrug, analog, isomer, metabolite, derivant, the acceptable salt of pharmacy, medicine, polymorph, crystal, impurity, N-oxide, hydrate or its combination in any of representing by the structure of formula (III):
In another embodiment, the invention provides SARM (SARM) chemical compound or its prodrug, analog, isomer, metabolite, derivant, the acceptable salt of pharmacy, medicine, polymorph, crystal, impurity, N-oxide, hydrate or its combination in any of representing by formula (IV) structure:
Figure A20058001846800162
Wherein X is O;
T is OH, OR, NHCOCH 3, NHCOR or OC (O) R;
Z is H, alkyl, NO 2, CN, COOH, COR, NHCOR or CONHR;
Y is H, alkyl, CF 3, halogen, hydroxyl-alkyl or alkyl aldehydes;
A is selected from following group:
Wherein
R 2, R 3, R 4, R 5, R 6Be H, halogen, CN, NO independently 2, NHCOCF 3
R is alkyl, haloalkyl, dihalo alkyl, tri haloalkyl, CH 2F, CHF 2, CF 3, CF 2CF 3, aryl, phenyl, halogen, thiazolinyl or OH; And
R 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 para-position, and perhaps in another embodiment, Y is in a position, perhaps in another embodiment, and their combination in any.
In one embodiment, the invention provides a kind of pharmaceutical composition, it contains formula (I), (II), (III) or chemical compound (IV) or its prodrug, analog, isomer, metabolite, derivant, the acceptable salt of pharmacy, medicine, polymorph, crystal, impurity, N-oxide, hydrate or its combination in any and suitable carriers or diluent.
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, alkoxy carbonyl group, acylamino-, alkyl amido, dialkyl group acylamino-, nitro, amino, alkyl amino, 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, acrylic, cyclobutenyl, cyclohexenyl group etc.Thiazolinyl can be unsubstituted or is selected from following group and replace by one or more: halogen, hydroxyl, alkoxy carbonyl group, acylamino-, alkyl amido, dialkyl group acylamino-, nitro, amino, alkyl amino, 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, in another embodiment by Cl, 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, alkoxy carbonyl group, acylamino-, alkyl amido, dialkyl group acylamino-, nitro, amino, alkyl amino, dialkyl amido, carboxyl or sulfo-or alkylthio.The limiting examples of aromatic ring is phenyl, naphthyl, pyranose, pyrrole radicals, pyrazinyl, pyrimidine radicals, pyrazolyl, pyridine radicals, furyl, thienyl, thiazolyl, imidazole radicals, isoxazolyl etc.
" hydroxyl " refers to the OH group.It will be appreciated by those skilled in the art that when the T in the chemical compound of the present invention is OR R is not OH.
In one embodiment, term " halogen (halo) " or " halogen (halogen) " refer to refer to Cl in another embodiment by F in one embodiment, refer to Br in another embodiment, or refer to I in another embodiment.
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 a benzyl.
In one embodiment, the invention provides SARM chemical compound and/or its analog, derivant, isomer, metabolite, the acceptable salt of pharmacy, medicine, hydrate, N-oxide, prodrug, polymorph, impurity or crystal or its combination in any.In another embodiment, the invention provides the analog of SARM chemical compound.In another embodiment, the invention provides the derivant of SARM chemical compound.In another embodiment, the invention provides the isomer of SARM chemical compound.In another embodiment, the invention provides the metabolite of SARM chemical compound.In another embodiment, the invention provides the acceptable salt of pharmacy of SARM chemical compound.In another embodiment, the invention provides the medicine of SARM chemical compound.In another embodiment, the invention provides the hydrate of SARM chemical compound.In another embodiment, the invention provides the N-oxide of SARM chemical compound.In another embodiment, the invention provides the prodrug of SARM chemical compound.In another embodiment, the invention provides the polymorph of SARM chemical compound.In another embodiment, the invention provides the crystal of SARM chemical compound.In another embodiment, the invention provides the impurity of SARM chemical compound.In another embodiment, the invention provides and contain the SARM compound compositions, the acceptable salt of analog, derivant, isomer, metabolite, pharmacy, medicine, hydrate, N-oxide, prodrug, polymorph, impurity or the crystalline combination of SARM chemical compound of the present invention are provided perhaps in another embodiment.
In one embodiment, term " isomer " includes but not limited to optical isomer and analog, constitutional isomer and analog, conformer and analog etc.
In one embodiment, term " isomer " refers to comprise the optical isomer of SARM chemical 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 chemical compounds can also show polymorphism.Should understand and the present invention includes any raceme, optically-active, polymorphic or stereoisomer form, or their mixture, these forms have the character that is used for the treatment of androgen 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 isomers.In another embodiment, SARM contains the 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 isolation).
The present invention includes SARM of the present invention " the acceptable salt of pharmacy ", can use amino SARM and the organic and mineral acid that replaces in one embodiment, for example citric acid and hydrochloric acid prepare the acceptable salt of described pharmacy.In another embodiment, the acceptable salt of pharmacy can also be by preparing with inorganic base such as naoh treatment phenolic compounds.In another embodiment, can be by prepare the ester of phenolic compounds with aliphatic series and aromatic carboxylic acid such as acetic acid and benzoate.
The present invention also comprises the amino substituent N-oxide of SARM described herein.
The invention provides the derivant of SARM chemical compound.In one embodiment, " derivant " includes but not limited to ether derivant, acid derivative, amide derivatives, ester derivant etc.In another embodiment, the present invention also comprises the hydrate of SARM chemical 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 chemical compound.In one embodiment, " metabolite " means any material that is produced by metabolism or metabolic process by another kind of material.
In other embodiments, the present invention also provides the medicine of SARM chemical compound.In other embodiments, term " medicine " refers to the compositions (pharmaceutical composition) that is suitable for pharmaceutical applications as described herein.
Selective androgen regulator (SARM)
SARM (SARM) is a class androgen receptor targeting agent (ARTA), and they show the short hero and the anabolic activity of the on-steroidal part of androgen receptor.These new activating agents are used for the male and treat the relevant disease of various hormones such as sexual dysfunction, libido reduction, erection disturbance, hypogonadism, muscle minimizing disease, osteopenia, osteoporosis, cognition and mood change, depression, anemia, alopecia, obesity, benign prostatic hyperplasia and/or carcinoma of prostate.In addition, SARM is used for oral androgenic replacement therapy and carcinoma of prostate imaging.In addition, SARM is used for that the women treats the relevant disease of various hormones such as sexual dysfunction, libido reduction, hypogonadism, muscle reduces disease, osteopenia, osteoporosis, cognition and mood change, depression, anemia, alopecia, obesity, endometriosis, breast carcinoma, uterus carcinoma and ovarian cancer.
Consider as this paper, the invention provides class SARM (SARM) chemical compound.These chemical compounds that are used to prevent and treat wasting disease and bone photo related disorders are classified as androgen receptor agonist (AR agonist), partial agonist or androgen receptor antagonists (AR antagonist).
Receptor stimulating agent 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.As this paper institute illustration, in some embodiments, SARM chemical compound of the present invention has the tissue selectivity effect, and for example wherein single activating agent is agonist, partial agonist and/or antagonist, and this depends on the tissue that this receptor is expressed.For example, but SARM chemical compound stimulated muscle tissue and suppress prostata tissue simultaneously.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 chemical compound of the present invention is that the AR agonist or the algoscopy 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 and seminal vesicle to determine by adopting gravimetry to monitor the SARM chemical compound.The AR antagonistic activity can be determined by the ability that monitoring SARM chemical compound suppresses to contain the growth of AR tissue.
In another embodiment, SARM chemical compound of the present invention can classify as part A R 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 chemical 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 chemical compound of estrogen receptor activity.In one embodiment, SARM is an agonist, perhaps in another embodiment, is antagonist.
In one embodiment, SARM has antagonistic activity in the gonad 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 levator ani m. muscular tissue, as illustrated among Fig. 3,4 or 5.
In one embodiment, SARM chemical 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 chemical compound is reversibly in conjunction with androgen receptor.In another embodiment, the SARM chemical compound is irreversibly in conjunction with androgen receptor.Chemical compound of the present invention can contain the functional group's (for example affinity tag) that makes androgen receptor alkylation (being the covalent bond form).Therefore, in the case, this chemical 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 chemical compound by receptor 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 chemical compound by receptor 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 to receptor relevant on the function in another embodiment, 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 steroid generation approach, perhaps in another embodiment, interact with other cell surface molecule that participates in metabolic pathway.
In one embodiment, the present invention also provides the compositions that contains a kind of SARM of the present invention, perhaps in another embodiment, contains the compositions of multiple SARM of the present invention.
In one embodiment, described compositions is a pharmaceutical composition, in another embodiment, it is pill, tablet, capsule, micronization or non-micronization capsule, solution, suspensoid, Emulsion, elixir, gel, emulsifiable paste, suppository or parenteral administration.
In one embodiment, the micronization capsule contains the granule that comprises SARM of the present invention, and term wherein used herein " micronization " refers to that particle diameter is less than 100 microns granule, 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 way (for example pin or conduit) that recombinant virus/compositions can be delivered to tissue by sending in (i.v.), intramuscular (i.m.) in the blood vessel, intranasal (i.n.), subcutaneous (s.c.), Sublingual, oral, rectum, the sheath.Perhaps, topical can expect to be applied to mucomembranous cell, be used for skin or the eye use.Another kind of administering mode is to give through inhalant or aerosol formulation.
For giving mammal, 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 compositions that gives can be a sterile solution, perhaps in another embodiment, can be aqueous solution or non-aqueous solution, suspension or emulsion.In one embodiment, described compositions can contain propylene glycol, Polyethylene Glycol, injectable organic ester such as ethyl oleate or cyclodextrin.In another embodiment, described compositions also can contain wetting agent, emulsifying agent and/or dispersant.In another embodiment, described compositions also can contain sterilized water or other sterile injectable medium arbitrarily.
In one embodiment, compositions of the present invention can comprise SARM of the present invention or its combination in any and the acceptable excipient of one or more pharmacy.
In one embodiment, " pharmaceutical composition " can refer to treat one or more chemical compounds of the present invention and the suitable excipient and/or the carrier that are used for method of the present invention of effective dose.In one embodiment, described compositions will contain the SARM of the present invention that treats effective dose.In one embodiment, term " treatment effective dose " can refer to given condition and give the amount that scheme provides therapeutical effect.In one embodiment, described compositions can be passed through any method afford known in the art.
In one embodiment, compositions of the present invention is mixed with oral or parenteral dosage forms, as uncoated tablets, coated tablet, pill, capsule, powder, granule, dispersion or suspensoid.In another embodiment, compositions of the present invention is mixed with for intravenous administration.In another embodiment, chemical compound of the present invention is formulated as ointment, emulsifiable paste or the gel form for percutaneous dosing.In another embodiment, chemical compound of the present invention is mixed with aerosol or the spray for nasal administration.In another embodiment, compositions 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 compositions.The example of suitable solid carrier comprises lactose, sucrose, gelatin and agar.Peroral dosage form can contain suitable bonding, lubricant, diluent, disintegrating agent, coloring agent, flavoring agent, flow-induction agent and fusing agent.For example liquid dosage form can contain suitable solvent, antiseptic, emulsifying agent, suspending agent, diluent, sweeting agent, thickening agent and fusing agent.Parenteral and intravenous form also comprise mineral and other material so that they and selected injection or delivery system type are compatible.Certainly, also can use other excipient.
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, chemical compound of the present invention and compositions 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 compositions.In another embodiment, described compositions also can contain other active component, and the activity of described other active component is useful for the application-specific that the SARM chemical compound is just giving.
In one embodiment, the invention provides ASARM chemical compound of the present invention or its prodrug, analog, isomer, metabolite, derivant, the acceptable salt of pharmacy, medicine, polymorph, crystal, impurity, N-oxide, hydrate or its combination in any 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 to suppress osteoclast generates.In one embodiment, the described SARM chemical compound chemical compound that is formula I as herein described, II, III or IV.
In one embodiment, described bone photo related disorders is a hereditary, and perhaps in another embodiment, described bone photo related disorders is as the result of given treatment of diseases scheme 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 carcinoma of prostate in the individuality is reacted.
In one embodiment, the invention provides the application that the SARM chemical compound is used for preventing individuality bone photo related disorders.In another embodiment, the invention provides the application that the SARM chemical compound is used for suppressing individuality bone photo related disorders.In another embodiment, the invention provides the application that the SARM chemical compound is used for suppressing individuality bone photo related disorders.In another embodiment, described SARM chemical compound is formula (I), (II), (III) or chemical compound (IV).In another embodiment, described SARM chemical compound is formula (I), (II), (III) or chemical compound (IV) or its prodrug, analog, isomer, metabolite, derivant, the acceptable salt of pharmacy, medicine, polymorph, crystal, impurity, N-oxide, hydrate or its combination in any.
In one embodiment, described bone photo related disorders is an osteoporosis.In another embodiment, described bone photo related disorders is an osteopenia.In another embodiment, described bone photo related disorders is that bone resorption increases.In another embodiment, described bone photo related disorders is a fracture.In another embodiment, described bone photo related disorders is the bone fragility.In another embodiment, described bone photo related disorders is that BMD reduces.In another embodiment, described bone photo related disorders is the combination in any that osteoporosis, osteopenia, bone resorption increase, fracture, bone fragility and BMD reduce.Every kind of disease is all represented 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 bone fragility increase as a result 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 the unusual or bone density decline of sclerotin in one embodiment.In another embodiment, do not cause slightly falling down or damage just may make and getting involved of fracture under normal conditions in osteoporotic osteogenesis fracture.In one embodiment, fracture can be the form (as hip fracture) of crackle or the form (as the compression fracture of spinal column) 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 motility to reduce without inhibition.
In one embodiment, osteoporosis is caused by androgen-deprivation.In another embodiment, osteoporosis takes place with androgen-deprivation.In another embodiment, osteoporosis is a primary osteoporosis.In another embodiment, osteoporosis is a secondary osteoporosis.In another embodiment, osteoporosis is a postmenopausal osteoporosis.In another embodiment, osteoporosis is the teenager osteoporosis.In another embodiment, osteoporosis is an idiopathic osteoporosis.In another embodiment, osteoporosis is a senile osteoporosis.
In another embodiment, primary osteoporosis is an I type primary osteoporosis.In another embodiment, primary osteoporosis is an II type primary osteoporosis.Every type osteoporosis is all represented 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 micro structure and degenerate.In one embodiment, " micro structure degeneration " be meant that bone trabecula attenuates and lose being connected between (the following definition) and bone trabecula.In another embodiment, " osteoporosis " is defined as BMD and is lower than 2.5 standard deviations (SD) of Young Adults meansigma methods or lower.In another embodiment, " osteoporosis " is defined as BMC and is lower than 2.5 SD of Young Adults meansigma methods or lower.In another embodiment, " osteoporosis " is defined as BMD and is lower than 2.0 SD of Young Adults meansigma methods or lower.In another embodiment, " osteoporosis " is defined as BMC and is lower than 2.0 SD of Young Adults meansigma methods or lower.In another embodiment, " osteoporosis " is defined as BMD and is lower than 3.0 SD of Young Adults meansigma methods or lower.In another embodiment, " osteoporosis " is defined as BMC and is lower than 3.0 SD of Young Adults meansigma methods or lower.Independent embodiment of the present invention is all represented in osteoporosis or osteopenic every kind of definition.
In another embodiment, " osteoporosis " is defined as 2.5 SD that BMD is lower than the Young Adults meansigma methods.In another embodiment, " osteoporosis " is defined as 2.5 SD that BMC is lower than the Young Adults meansigma methods.In another embodiment, " osteoporosis " is defined as 2.0 SD that BMD is lower than the Young Adults meansigma methods.In another embodiment, " osteoporosis " is defined as 2.0 SD that BMC is lower than the Young Adults meansigma methods.In another embodiment, " osteoporosis " is defined as the 3.0SD that BMD is lower than the Young Adults meansigma methods.In another embodiment, " osteoporosis " is defined as 3.0 SD that BMC is lower than the Young Adults meansigma methods.Independent embodiment of the present invention is all represented in osteoporotic every kind of definition.
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 meansigma methods of the Young Adults bone amount peak value 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 T value and is lower than 2.5 SD of Young Adults meansigma methods or lower.In another embodiment, " osteoporosis " is defined as the Z value and is lower than 2.5 SD of Young Adults meansigma methods or lower.In another embodiment, " osteoporosis " is defined as T value and is lower than 2.0 SD of Young Adults meansigma methods or lower.In another embodiment, " osteoporosis " is defined as the Z value and is lower than 2.0 SD of Young Adults meansigma methods or lower.In another embodiment, " osteoporosis " is defined as T value and is lower than 3.0 SD of Young Adults meansigma methods or lower.In another embodiment, " osteoporosis " is defined as the Z value and is lower than 3.0 SD of Young Adults meansigma methods or lower.
In another embodiment, " osteoporosis " is defined as 2.5 SD that T value is lower than the Young Adults meansigma methods.In another embodiment, " osteoporosis " is defined as 2.5 SD that the Z value is lower than the Young Adults meansigma methods.In another embodiment, " osteoporosis " is defined as 2.0 SD that T value is lower than the Young Adults meansigma methods.In another embodiment, " osteoporosis " is defined as 2.0 SD that the Z value is lower than the Young Adults meansigma methods.In another embodiment, " osteoporosis " is defined as 3.0 SD that T value is lower than the Young Adults meansigma methods.In another embodiment, " osteoporosis " is defined as the 3.0SD that the Z value is lower than the Young Adults meansigma methods.Independent embodiment of the present invention is all represented in osteoporotic every kind of definition.
In one embodiment, term " BMD " is meant the measurement value of calculation of actual bone amount.The absolute magnitude of the bone of measuring by BMD usually and bone strength and weight capacity thereof have dependency.As measure the risk that blood pressure can help to predict apoplexy, can predict the risk that fracture takes place by measuring BMD.
In one embodiment, BMD can survey and draw (mapping) commercial measurement by BMD.In one embodiment, the bone density of hipbone, spine, carpal bone or calcaneus can be measured by multiple technologies.The method for optimizing 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 takes place, but is the best information of this position fracture of prediction from the information that specific part obtains.Quantitative Analysis machine control tomography (QCT) also is used to measure the BMD of spine.Referring to for example " NuclearMedicine: " Quantitative Procedures " Walmer H W etc., Toronto Little, Brown﹠amp; Co. publish 1983, the 107-132 pages or leaves; " Assessment ofBone MineralPart 1, " J Nucl Medicine, pp 1134-1141 (1984); And " Bone MineralDensity ofThe Radius " J Nucl Medicine 26:13-39 (1985).Measure every kind of method of BMD and all represent independent embodiment of the present invention.
In one embodiment, " osteopenia " refers to that BMD or BMC are lower than the 1-2.5 SD of Young Adults meansigma methods.In another embodiment, " osteopenia " phalanges calcification or bone density reduce.In one embodiment, all skeletal systems that this disease is arranged contained in this term.Every kind of disease disclosed by the invention definition or diagnostic method are all represented 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 fragility " the fragile state of instigating bone to be easy to fracture.
In one embodiment, described bone photo related disorders is with SARM chemical 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 individual other bony spur afterwards and intensify compound.In one embodiment, described bony spur intensifies compound and can contain natural or synthetic material.
In one embodiment, as the skilled artisan will appreciate, described bony spur intensifies compound can comprise bone morphogenetic protein (BMP), somatomedin such as epidermal growth factor (EGF), fibroblast growth factor (FGF), transforming growth factor (TGF-α or TGF-β), insulin-like growth factor (IGF), platelet derived growth factor (PDGF), Hedgelog protein such as sound hedgehog albumen (sonic hedgehog), porcupine albumen (indian hedgehog) and desert Rrinaceus earopaeus (deserthedgehog), hormone such as follicle stimulating hormone, parathyroid hormone, parathyroid hormone-related peptide, activin, inhibin, frizzled albumen, frzb albumen or frazzled albumen, BMP is conjugated protein as chordin and myosin, cytokine such as IL-3, IL-7, GM-CSF, chemotactic factor such as eotaxin, collagen protein, osteocalcin, osteonectin etc.
In another embodiment, the compositions 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 bony spur intensifies compound and bone growth promoting cell.In one embodiment, the bone growth promoting cell can be stem cell or CFU-GM, and it can be induced to differentiate into osteoblast.In another embodiment, described cell can be an osteoblast.
In another embodiment, the nucleic acid that coding bony 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 disease or disease are by hormone disturbance, destruction or unbalance causing.In another embodiment, these diseases do not rely on hormone disturbance, destruction or unbalance and take place.Every kind of probability is all represented 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 a steroid hormone.In another embodiment, described hormone is an estrogen.In another embodiment, described hormone is an androgen.In another embodiment, described hormone is a glucocorticoid.In another embodiment, described hormone is a corticosteroid.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 disease.For example, described hormonoprivia can be the result who loses as androgen in the individuality that causes of the individual carcinoma of prostate of treatment.
Every kind of probability is all represented independent embodiment of the present invention.
In one embodiment, the invention provides the application that the SARM chemical compound is used to increase individual bone strength.In another embodiment, described SARM chemical compound is formula (I), (II), (III) or chemical compound (IV).In another embodiment, described SARM chemical compound is formula (I), (II), (III) or chemical compound (IV) or its prodrug, analog, isomer, metabolite, derivant, the acceptable salt of pharmacy, medicine, polymorph, crystal, impurity, N-oxide, hydrate or its combination in any.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 application that the SARM chemical compound is used to increase individual bone amount.In another embodiment, described SARM chemical compound is formula (I), (II), (III) or chemical compound (IV).In another embodiment, described SARM chemical compound is formula (I), (II), (III) or chemical compound (IV) or its prodrug, analog, isomer, metabolite, derivant, the acceptable salt of pharmacy, medicine, polymorph, crystal, impurity, N-oxide, hydrate or its combination in any, or contains its compositions.
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 cachexia.In another embodiment, method of the present invention is provided for increasing individual bone amount, and described bone amount is a cortical bone bone amount.In another embodiment, described bone amount is a trabecular bone bone amount.In another embodiment, described bone amount is the Grafting Cancellous Bone Bolt amount.
In one embodiment, the invention provides the SARM chemical compound and be used to promote osteoplastic application.In another embodiment, described SARM chemical compound is formula (I), (II), (III) or chemical compound (IV).In another embodiment, described SARM chemical compound is formula (I), (II), (III) or chemical compound (IV) or its prodrug, analog, isomer, metabolite, derivant, the acceptable salt of pharmacy, medicine, polymorph, crystal, impurity, N-oxide, hydrate or its combination in any, perhaps contains its compositions.
In another embodiment, described SARM chemical compound stimulates or is enhanced to osteocyte and generates.In another embodiment, described SARM chemical compound suppresses osteoclast propagation.
In one embodiment, the invention provides the osteogenesis that stimulates or strengthen propagation through osteoblast.In one embodiment, term " osteoblast " refers to participate in osteogenetic cell.In one embodiment, but participate in osteogenetic osteoblast formative tissue, mineral deposit wherein makes bone have intensity.In another embodiment, the invention provides, perhaps in another embodiment, provide through suppressing the osteogenesis of osteoclast activity through suppressing the inductive osteogenesis of osteoclast.In one embodiment, term " osteoclast " refers to participate in bone to be rebuild, particularly the cell of bone resorption.
In one embodiment, osteopathia or disease are treated through stimulating osteogenesis by method of the present invention.In another embodiment, treatment of the present invention provides the bone amount that keeps.Balance between the 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 and keeps described equilibrated method.
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 the direct effect of SARM to osteoblast and osteoclast, and it is useful in increasing sufferers of osteoporosis face bone amount.
In one embodiment, the invention provides SARM chemical compound of the present invention or its prodrug, analog, isomer, metabolite, derivant, the acceptable salt of pharmacy, medicine, polymorph, crystal, impurity, N-oxide, hydrate or its combination in any 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 muscle protein catabolism that treatment, prevention, inhibition, minimizing or compacting are caused by wasting disease.In one embodiment, described SARM chemical compound is formula as herein described (I), (II), (III) or chemical compound (IV).In another embodiment, the invention provides and contain the SARM compound compositions of the present invention that is useful on methods described herein.
In one embodiment, the invention provides the application that the SARM chemical compound is used for the treatment of the individuality of suffering from wasting disease.In another embodiment, described SARM chemical compound is formula (I), (II), (III) or chemical compound (IV).In another embodiment, described SARM chemical compound is formula (I), (II), (III) or chemical compound (IV) or its prodrug, analog, isomer, metabolite, derivant, the acceptable salt of pharmacy, medicine, polymorph, crystal, impurity, N-oxide, hydrate or its combination in any, perhaps contains its compositions.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 chemical compound comprises the pharmaceutical composition that contains the SARM chemical compound.In another embodiment, giving step comprises and gives described individuality with described pharmaceutical composition intravenous, intra-arterial or the intramuscular injection of liquid form; 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 the strength source.Three types muscle is arranged in vivo: a) skeletal muscle-end of responsible mobile body and the muscle of perimeter; B) cardiac muscle-cardiac muscle; C) muscle of smooth muscle-in arterial wall and intestinal wall.
The disease of becoming thin herein or disease are defined as at least, and Partial Feature is disease or the disease that unusual, gradual health, organ or tissue's weight reduce.The disease of becoming thin can be used as pathology, takes place 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 taking place of long-term bed or extremity degenerate with sexual function.The disease of becoming thin also may be that the age is relevant.The feature that loses weight that takes place during the disease 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 histone causes or the loss of muscle quantities.
In one embodiment, " wasting (muscle wasting) " used herein or " wasting (muscular wasting) " are used interchangeably, and refer to the gradual loss of muscle quantities and/or skeleton or voluntary muscle, the cardiac muscle of control heart and the gradual unable and degeneration of smooth muscle that muscle comprises controlled motion.In one embodiment, described wasting disease or disease are chronic wasting disease or disease." chronic wasting disease " is defined as chronic (promptly continuing) gradual loss of muscle quantities and/or the chronic gradual unable and degeneration of muscle at this paper in long-time.
The feature of the muscle quantities loss that takes place during wasting disease can be to decompose or degraded through the catabolic myogen of myogen.The reason that the albuminolysis metabolism takes place is high unusually protein degradation speed, low albumen synthesis rate or the combination of the two unusually.The albuminolysis metabolism no matter be to be caused or caused by low albumen aggregate velocity by the high protein degree of degradation, all causes muscle quantities to reduce brownization and wasting disease.Term " catabolism " has implication as known in the art, particularly refers to metabolic energy burning form.
The result that wasting disease can be used as pathology, disease, slight illness or disease takes place.In one embodiment, described pathology, slight illness, disease or disease are chronic.In another embodiment, described pathology, slight illness, disease or disease are genetic.In another embodiment, described pathology, slight illness, disease or disease are neuropathic.In another embodiment, described pathology, slight illness, disease or disease are infective.As described herein, the pathology that chemical compound of the present invention and compositions give, disease, the patient's condition or disease are the disease that directly or indirectly produces muscle quantities consumption (i.e. loss), i.e. wasting disease.
In one embodiment, wasting disease is that individuality suffers from muscular dystrophy in the individuality; Amyotrophy; The chain ridge bulbar muscular atrophy of X (SBMA); Cachexia; Malnutrition; Tuberculosis; Leprosy; Diabetes; Nephropathy; Chronic obstructive pulmonary disease (COPD); Cancer; The renal failure in latter stage; Muscle reduces disease; Emphysema; Osteomalacia; Or myocardiac result.
In another embodiment, described wasting disease is owing to enterovirus, Epstein-Barr virus, herpes zoster, HIV, trypanosomicide, influenza, Coxsackie virus, rickettsia, trichinella, schistosomicide, mycobacterial infections cause.
Muscular dystrophy is hereditary, it is characterized in that the skeletal muscle or the gradual unable and degeneration of voluntary muscle of controlled motion.Cardiac muscle and some other non-voluntary muscles are also got involved in the muscular dystrophy of some types.The main type of muscular dystrophy (MD) is: Duchenne muscular dystrophy, myotonia atrophica, Duchenne muscular dystrophy, Becker muscular dystrophy, limb girdle type malnutrition, facio-scapulo-humeral type muscular dystrophy, congenital muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy and Emery-Dreifuss muscular dystrophy.
Muscular dystrophy may influence the crowd of institute's has age.Though some types begin the baby or the childhood period become obviously, other type is until the middle age or just obvious later on.Du Xing Shi MD is modal type, particularly influences the child.Myotonia atrophica is that these diseases are modal in the adult.
Amyotrophy (MA) is characterised in that wasting or minimizing and muscle quantities reduce.For example, MA is the wasting disease of taking place 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 influences the male, 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 the androgen level, 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.
Cachexia be cause by disease or as the weak of the seondary effect of disease with lose weight.The heart cachexia, promptly the myogen of cardiac muscle and skeletal muscle is become thin, and is a feature of congestive heart failure.Cancer cachexia is the syndrome that takes place 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.
Cachexia also sees acquired immune deficiency syndrome (AIDS) (AIDS), and myopathy that HIV (human immunodeficiency virus) (HIV) is relevant and/or myasthenia/become thin are the common relatively clinical manifestations of AIDS.The individuality experience of suffering from relevant myopathy of HIV or myasthenia or becoming thin is lost weight significantly, general or centration myasthenia, tenderness or amyotrophy.
It is a kind of wasting diseases that torments senile chronic disease patient that muscle reduces disease, it is characterized in that the minimizing of muscle quantities and the forfeiture of function.And the increase of lean body 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 cause in the old-age group by wasting.Along with health is aging, skeletal muscle is increased by the displaced ratio of fibrous tissue.Consequently muscle strength, performance and endurance obviously descend.
Because it is ailing or damage causes is in hospital or for example also can causes wasting disease with the sexual function degeneration when giving up of taking place fixedly time of limbs for a long time.Studies show that and suffer from damage, persistent one-sided wasting arranged in the long-term inpatient of chronic pain, burn, wound or cancer that lean body mass reduces as a result.
Central nervous system's (CNS) damage 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 cord injury or infringement.
In another embodiment, wasting is crapulent result, and the chemical compound of the present invention and the compositions of available representative embodiment of the present invention are treated.
In one embodiment, the invention provides the application that the SARM chemical compound is used to prevent individual wasting disease.In another embodiment, described SARM chemical compound is formula (I), (II), (III) or chemical compound (IV).In another embodiment, described SARM chemical compound is formula (I), (II), (III) or chemical compound (IV) or its prodrug, analog, isomer, metabolite, derivant, the acceptable salt of pharmacy, medicine, polymorph, crystal, impurity, N-oxide, hydrate or its combination in any.In another embodiment, administration comprises the pharmaceutical composition that contains described SARM and/or its prodrug, analog, derivant, isomer, metabolite, the acceptable salt of pharmacy, medicine, hydrate, N-oxide or its combination in any and pharmaceutically acceptable carrier.Thereby, the wasting disease that prevention is individual.
In one embodiment, the invention provides the application that the SARM chemical compound is used for the treatment of the wasting disease relevant with chronic disease.In another embodiment, described SARM chemical compound is formula (I), (II), (III) or chemical compound (IV).In another embodiment, described SARM chemical compound is formula (I), (II), (III) or chemical compound (IV) or its prodrug, analog, isomer, metabolite, derivant, the acceptable salt of pharmacy, medicine, polymorph, crystal, impurity, N-oxide, hydrate or its combination in any, or contains its compositions.In another embodiment, described SARM application of compound is the described individuality of orally give.
In one embodiment, the invention provides the application that the SARM chemical compound is used to prevent individual wasting disease.In another embodiment, suppress individual wasting disease.In another embodiment, suppress individual wasting disease.In another embodiment, reduce the incidence rate of individual wasting disease.In another embodiment, described SARM chemical compound is formula (I), (II), (III) or chemical compound (IV).In another embodiment, described SARM chemical compound is formula (I), (II), (III) or chemical compound (IV) or its prodrug, analog, isomer, metabolite, derivant, the acceptable salt of pharmacy, medicine, polymorph, crystal, impurity, N-oxide, hydrate or its combination in any, or contains its compositions.
In another embodiment, the invention provides SARM chemical compound of the present invention or its prodrug, analog, isomer, metabolite, derivant, the acceptable salt of pharmacy, medicine, polymorph, crystal, impurity, N-oxide, hydrate or its combination in any, or contain the application that its compositions is used for the treatment of, prevents, suppresses, suppresses individual wasting disease or reduces the incidence rate of individual wasting disease.
In another embodiment, the invention provides SARM chemical compound of the present invention or its prodrug, analog, isomer, metabolite, derivant, the acceptable salt of pharmacy, medicine, polymorph, crystal, impurity, N-oxide, hydrate or its combination in any, or contain its application of compositions in increasing individual muscle behavior performance, muscle size, muscular strength or its combination in any.
In another embodiment, SARM chemical compound of the present invention and compositions are used to promote or quicken recovery behind the operation technique.
In one embodiment, the invention provides the application that the SARM chemical compound is used to reduce individual fat mass.In another embodiment, described SARM chemical compound is formula (I), (II), (III) or chemical compound (IV).In another embodiment, described SARM chemical compound is formula (I), (II), (III) or chemical compound (IV) or its prodrug, analog, isomer, metabolite, derivant, the acceptable salt of pharmacy, medicine, polymorph, crystal, impurity, N-oxide, hydrate or its combination in any, or contains its compositions.
In another embodiment, the invention provides SARM chemical compound of the present invention, for example have chemical compound or its prodrug, analog, isomer, metabolite, derivant, the acceptable salt of pharmacy, medicine, polymorph, crystal, impurity, N-oxide, hydrate or its combination in any of formula (I), (II), (III) or structure (IV), or the compositions that contains it is in individual obesity relevant with metabolism syndrome of treatment or the application in the diabetes.
In one embodiment, described individuality suffers from hormone imbalances, disorder or disease.In another embodiment, described individuality is the menopause individuality.
In one embodiment, the invention provides the SARM chemical compound and be used to increase individual thin heavy application.In another embodiment, described SARM chemical compound is formula (I), (II), (III) or chemical compound (IV).In another embodiment, described SARM chemical compound is formula (I), (II), (III) or chemical compound (IV) or its prodrug, analog, isomer, metabolite, derivant, the acceptable salt of pharmacy, medicine, polymorph, crystal, impurity, N-oxide, hydrate or its combination in any.Thereby, increase individual thin heavy.
In another embodiment, described individuality suffers from hormone imbalances, disorder or disease.In another embodiment, described individuality is the menopause individuality.
Fig. 3-7 shows that compound III is excito-anabolic and has minimum short male actively that thereby these chemical compounds can be used for treatment, and wherein to pass by androgen be incompatible patient group.No matter proved testosterone whether in the presence of the equal stimulated muscle growth of compound III, simultaneously to prostate performance antiproliferative effect, thereby in one embodiment, SARM of the present invention recovers the muscle quantities that muscle reduces disease or cachexia patient's forfeiture.
In one embodiment, SARM of the present invention is through injecting the described pharmaceutical composition of liquid form to individual intravenous administration.In another embodiment, SARM of the present invention is through injecting the described pharmaceutical composition of liquid form to individual intra-arterial administration.In another embodiment, SARM of the present invention is through injecting the described pharmaceutical composition of liquid form to individual intramuscular administration.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 muscle protein 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 a mammalian subject.
In one embodiment, the present invention relates to prevent, suppress, suppress individual fat or reduce the method for individual fat incidence rate, it comprises and gives described individuality with effectively preventing, suppress, suppress individual SARM of the present invention (SARM) and/or its analog, derivant, isomer, metabolite, the acceptable salt of pharmacy, medicine, hydrate, N-oxide, prodrug, polymorph, crystal or its combination in any fat or that reduce the amount of individual fat incidence rate.
In one embodiment, SARM chemical compound of the present invention changes individual leptin (leptin) level.In another embodiment, the SARM chemical compound reduces leptin level.In another embodiment, SARM chemical 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 influences the cyclical level of leptin, perhaps in one embodiment, influences the level of organizing of leptin.In one embodiment, term " leptin level " refers to the serum levels of leptin.Consider all leptin is had effect in the external and body of SARM chemical compound of the present invention 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 measured in external test or body by any method known to those skilled in the art and determine.
Because leptin participates in control appetite, 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 rate be useful Therapeutic Method.The level of regulating leptin can cause individual appetite decline, food intake minimizing and energy expenditure to increase, thereby has the control of helping and treat fat.
In one embodiment, term " obesity " is defined as the restriction of the increase of body weight above skeleton and somagenic need, and the result is a fat excessive buildup in vivo.
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 disease.The limiting examples of described disease is osteoarthritis, type ii diabetes, hypertension, apoplexy and heart disease.
In another embodiment, term " osteoarthritis " refers to the degenerative joint disease of the main non-inflammation that takes place in the old people, it is characterized in that degeneration, hyperostosis and the synovial membrane edge of articular cartilage and synovial membrane change.In another embodiment, it is attended by pain and stiff, after the particularly long-time activity.
In one embodiment, term " diabetes " refers to that the relative or absolute shortage of insulin causes carbohydrate metabolism uncontrolled.Most patients can classify as insulin-dependent diabetes (IDDM or type i diabetes) or noninsulindependent diabetes (NIDDM or type ii diabetes) clinically.
In other embodiments, term " hypertension " or " hypertension " refer to the hypertension repeatedly 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 disease " refers to heart normal function and active malfunction, comprises heart failure.
In addition, proved recently androgen participate between the matter pluripotent cell be orientated myogenous cell system and stop and be divided into adipose cell lines (2003, Jul 24 for Singh etc., Endocrinology).Therefore, the SARM chemical compound can be used for blocking-up lipogenesis 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 analog, derivant, isomer, metabolite, the acceptable salt of pharmacy, medicine, hydrate, N-oxide, prodrug, polymorph, crystal or its combination in any 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 analog, derivant, isomer, metabolite, the acceptable salt of pharmacy, medicine, hydrate, N-oxide, prodrug, polymorph, crystal or its combination in any 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 analog, derivant, isomer, metabolite, the acceptable salt of pharmacy, medicine, hydrate, N-oxide, prodrug, polymorph, crystal or its combination in any give described individuality.In one embodiment, change body composition and comprise lean body 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 body mass or fat free body weight, it comprises and will effectively change the SARM of the present invention (SARM) of amount of individual lean body mass or fat free body weight and/or the step that its analog, derivant, isomer, metabolite, the acceptable salt of pharmacy, medicine, hydrate, N-oxide, prodrug, polymorph, crystal or its combination in any 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 analog, derivant, isomer, metabolite, the acceptable salt of pharmacy, medicine, hydrate, N-oxide, prodrug, polymorph, crystal or its combination in any 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 of treatment is relevant and/or the step that its analog, derivant, isomer, metabolite, the acceptable salt of pharmacy, medicine, hydrate, N-oxide, prodrug, polymorph, crystal or its combination in any 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 analog, derivant, isomer, metabolite, the acceptable salt of pharmacy, medicine, hydrate, N-oxide, prodrug, polymorph, crystal or its combination in any give described individuality.
In one embodiment, the metabolic disorder that described obesity is relevant is a hypertension.In another embodiment, described disease is an osteoarthritis.In another embodiment, described disease is a type ii diabetes.In another embodiment, described disease is hypertension.In another embodiment, described disease is an apoplexy.In another embodiment, described disease is a heart disease.
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 analog, derivant, isomer, metabolite, the acceptable salt of pharmacy, medicine, hydrate, N-oxide, prodrug, polymorph, crystal or its combination in any 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 analog, derivant, isomer, metabolite, the acceptable salt of pharmacy, medicine, hydrate, N-oxide, prodrug, polymorph, crystal or its combination in any 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 analog, derivant, isomer, metabolite, the acceptable salt of pharmacy, medicine, hydrate, N-oxide, prodrug, polymorph, crystal or its combination in any 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 analog, derivant, isomer, metabolite, the acceptable salt of pharmacy, medicine, hydrate, N-oxide, prodrug, polymorph, crystal or its combination in any give described individuality.
In one embodiment, being used for following SARM is formula (I), (II), (III) or (IV) chemical 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 body mass or fat free body weight; F) fat is converted into lean meat; G) the individual fat relevant metabolic disorder of treatment, prevention, compacting, inhibition or minimizing, for example hypertension, osteoarthritis, type ii diabetes, hypertension, apoplexy or heart disease; H) reduce, suppress, suppress or reduce individual lipogenesis; I) change differentiation of stem cells; And/or j) changes leptin level.
In one embodiment, find that SARM chemical compound of the present invention makes progress in treatment or prevention diabetes, perhaps treats in the diabetic symptom useful.In another embodiment, SARM chemical compound of the present invention is used for the treatment of the relevant common disease of diabetes.These diseases comprise: hypertension, cerebrovascular disease, the atherosclerosis coronary artery disease, degeneration of macula, diabetic retinopathy (oculopathy) and blind, cataract-systemic inflammatory (being characterised in that inflammatory label such as erythrosedimentation speed or C-reactive protein raise), birth defect, the diabetes that gestation is relevant, preeclampsia and gestational hypertension, nephropathy (renal insufficiency, renal failure etc.), neuropathy (diabetic neuropathy), surface and whole body fungal infection, congestive heart failure, gout/hyperuricemia, fat, hypertriglyceridemia, hypercholesterolemia, dermatosis such as necrobiosis lipoidica diabeticorum (NLD) that fatty liver disease (non-alcoholic fatty liver disease or NASH) and diabetes are relevant, diabetic vesicle (diabetic blister disease), the dermexanthesis xanthomatosis, refer to sclerosis, dispersivity granuloma annulare and acanthosis nigricans.
In one embodiment, the invention provides and be used for following method: a) treatment, prevention, compacting, suppress atherosclerosis; B) treatment, prevention, compacting, inhibition are because the hepatic injury that lipidosis causes, it comprises and will effectively treat, prevent or suppress atherosclerosis and because SARM of the present invention (SARM) and/or its analog, derivant, isomer, metabolite, the acceptable salt of pharmacy, medicine, hydrate, N-oxide, prodrug, polymorph, crystal or its combination in any of the amount of the hepatic injury that causes of lipidosis, the compositions that perhaps contains it gives individual step.
In one embodiment, SARM chemical 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 lipidosis causes.
In one embodiment, refer to can be from innermost layer chronic, the complex disease that begin of infringement tremulous pulse for atherosclerosis.In another embodiment, the reason of infringement arterial wall can comprise that a) cholesterol levels raises in the blood; B) hypertension; C) smoke of tobacco; D) diabetes.In another embodiment, be true although smoke of tobacco may make atherosclerosis worsen more and quicken that it grows in coronary artery, large artery trunks and leg arteries, this disease is medicable in the smoker.Similarly, in another embodiment, method of the present invention can be used for treating the individuality with the angiopathy family medical history of making up one's mind the morning that increases the atherosclerosis risk.
In one embodiment, because the hepatic injury that causes of lipidosis refers to increasing of in the hepatocyte 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 the cicatrix and the sclerosis of liver.When cicatrix becomes extensive, be called cirrhosis.In another embodiment, athero becomes obesity in liver.In another embodiment, fatty liver is also relevant with excessive use ethanol with diabetes, hypertriglyceridemia.In another embodiment, fatty liver can with vitamin A excessive in some disease such as pulmonary tuberculosis and malnutrition, fat intestinal by-pass operation, the body or use some drugs such as valproic acid (trade name: Depakene/Depakote) and corticosteroid (cortisone, prednisone) take place.Sometimes fatty liver takes place 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, and perhaps in another embodiment, described individuality is the women.
In another embodiment, the compositions that the invention provides SARM of the present invention or contain it promote or the spermatogenesis of compacting male individual in application.SARM more of the present invention show short male active in addition, therefore stimulate spermatogenesis.In another embodiment, SARM of the present invention shows antagonistic activity in the gonad of individuality, therefore can suppress spermatogenesis.In one embodiment, therefore described SARM can be used as contraceptive.
Should understand, any application of SARM of the present invention, comprise particularly about with the application of muscle, fat, heart, liver, gonad or osseous tissue diseases associated or disease in application also be a part of the present invention, SARM chemical compound wherein of the present invention or contain the course of disease that gives advantageously to change these diseases or disease of its compositions.
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:
It is thin that SARM (SARM) compound III is divided into skeletonization to CFU-GM
The effect of born of the same parents and osteoclast
Material and method
Chemical drugs
Compound III, THT and PTH are with the prepared at concentrations 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 connective tissue on the femur, and in the minimum essential medium that contains penicillin, streptomycin and amphotericin B (MEM) in storing until cell culture on ice.
Medullary cell is cultivated
All cell culture materials 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.The femur two ends are all fractureed, and medullary cell washes in the 50ml conical pipe with the MEM that 15ml contains penicillin, streptomycin 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 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, among the MEM with the serum that does not contain phenol red and additional 15% active carbon desorption, penicillin, streptomycin, 300ng/ml amphotericin B, 0.28mM ascorbic acid and the 10mM β-phosphoglycerol of every hole 1,500,000 cell inoculations in 6 orifice plates, to break up to fibroblast/osteoblast system, and among the MEM with the amphotericin B of the serum that does not contain phenol red and additional 10% active carbon desorption, penicillin, streptomycin and the 300ng/ml of every hole 2,500,000 cell inoculations in 24 orifice plates, with to the differentiation of osteoclast system.Changed culture medium, and use described HORMONE TREATMENT in 2nd.Osteoclast is cultivated and is carried out in the presence of 50ng RANK part and 10ng GM-CSF to induce osteoclast to generate.Cultivate for osteoclast, changed culture medium every three days fully.Cultivate for osteoblast, changed half culture medium every three days to stay the somatomedin of emiocytosis.
Cell dyeing
When 12 end of day, for fibroblast cell cultures with cell fixation in 10% buffered formalin, and for the osteoclast culture with cell fixation in 4% formaldehyde.Fibroblast is used for alkaline phosphatase activities dyeing, uses spectrophotometer to measure O.D. as mentioned previously under 405nm.Osteoclast is used for anti-tartaic acid phosphatase activity (TRAP) dyeing, has the cell of 2 or more a plurality of nuclears and mapping as mentioned previously at the microscopically counting.
The result
SARM is the strong inductor of medullary cell to osteoblast and the differentiation of osteoclast system
Androgen has anabolic action to bone, for example lacks androgen among the androgen-deprivation of carcinoma of prostate treatment and the old people in some cases and has clearly illustrated that the benefit of androgen as bone protection hormone.Yet the androgenic use of dystopy is restricted owing to its side effect and owing to androgen is converted into estrogenic risk.
In order to determine whether SARM can have therapeutical effect and avoid above-mentioned side effect; have the ability of bone protective effect and side effect aspect still less (seen) with regard to SARM (SARM), various SARM are estimated as female hormone.Make the ability aspect of rat medullary cell of former generation with regard to dihydrotestosterone (DHT) and parathyroid hormone (PTH) and SARM compound III, the effectiveness and the SARM compound III of dihydrotestosterone (DHT) and parathyroid hormone (PTH) compared (Fig. 1 and 2) to osteoblast and the differentiation of osteoclast system.The above hormone exist or not in the presence of rat bone marrow cell was cultivated in culture medium 12, and be that the differentiation aspect is estimated to osteoblast and osteoclast with regard to them.
DHT and compound III all increase former generation medullary cell to the differentiation of osteoblast system, shown in alkali phosphatase (ALP) activity measurement of cell (Fig. 1).Under 1 μ M concentration, DHT and SARM induce suitable ALP activity, and under low concentration 100nM and 10nM, compound III shows to have bigger 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 handling with DHT or SARM significantly suppresses RANK part and the positive multinucleated osteoclast propagation of the inductive TRAP of GM-CSF.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 the anti-associating of absorbent fosamax again
Material and method
60 female, unpregnancies, complete 23 age in week the Sprague-Dawley rat (Wilmington MA) obtains from CharlesRiver Laboratories.Every cage is raised 2-3 animal, and adapts to 12-h illumination/dark cycle.Freely obtain food (7012C LM-485 Mus/rat sterilization diet, Harlan Teklad, Madison, WI) and water.The animal agreement of the research obtains the 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 made up of six following processed group: (1) complete+carrier, and (2) complete+compound III, (3) OVX+ carrier, (4) OVX+ compound III, (5) OVX+ fosamax, (6) OVX+ fosamax+compound III.DMSO: PEG300 (10: 90) vehicle group gives dosage (200L) through tube feed beginning on the 1st every day.Execution animal on the 45th in this research.Take out femur, remove soft tissue, and in SS saline soaked gauze, store until analysis down in-20 ℃.9 animal deads are arranged during studying.Complication and the technology mistake in oral administration (promptly being delivered in the lung) that these death cause owing to ovariectomy to drug solns.The dosage group is listed in table 1.
Group The gonad situation Handle Dosage Animal/group
1 2 3 4 5 6 Complete OVX OVX OVX OVX Carrier compound III carrier compound III Alendronate Alendronate compound III N/A 3mg/ day N/A 3mg/ day 1mg/ day+1mg/ day+3 mg/ day 9 9 7 8 10 8
Table 1, processed group
Fl is sent to SkeleTech Inc., and (Bothell WA) is used for biomechanical strength (three-point bending method) and pQCT and analyzes.Stratec XCT RM and related software (StratecMedizintechnik GmbH, Pforzheim, Germany.Software version 5.40 C) 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 0.5nm of femur major axis.Total bone mineral content, long-pending, the total bone mineral density of total surface of bone, cortical bone mineral content, cortical bone area, cortical 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 Instron Mechanical TestingMachine (it is 5500 that Instron 4465 has renovated), and (Canton on the pillar of the three-point bending device below in MA), faces down before making femur.The length (L) of a below intercolumniation is set at 14mm.Make the center in the device aligning femur stage casing of top load.Using constant displacement speed 6mm/min fractures until femur.The mechanical test instrument is directly measured maximum load (F u) (unit: N), stiffness (S) (unit: N/mm) can (W) (unit: mJ) with absorption.Axial area the moment of inertia (I) (unit: mm 4) calculate by the software in the femur stage casing pQCT analysis.Stress (σ) (unit: N/mm 2), elastic modelling quantity (E) (unit: Mpa) and intensity (T) (unit: mJ/m 3) calculate by following formula: stress: σ=(F u* L* (a/2))/(4*L); Elastic modelling quantity: 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 maximum load is measured by the 3-point bending method of femur.The result is presented among Fig. 3.Between complete vector (210N) matched group and OVX carrier (212N) matched group, do not observe difference.We observe the compound III processed group and compare with close set and OVX group respectively and have the trend that maximum load increases to 224 and 233 newton.Fosamax (213N) is compared with matched group with fosamax+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 matched group and OVX vehicle Control group, trabecular bone density is reduced to 215mg/cm from 379 respectively 3In the intact animal of handling with compound III, we observe slight the increasing of trabecular bone density and reach 398mg/cm 3In the OVX animal of handling with compound III, we observe with respect to OVX vehicle Control group and significantly increase to 406mg/cm 3The trabecular bone density that fosamax is handled increases to 480mg/cm 3The therapeutic alliance of fosamax 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
Material and method
The male Spargue-Dawley rat of heavily about 200g available from Harlan Bioproductsfor Science (Indianapolis, IN).Animal is kept 12 hours illumination/dark cycles, and can freely obtain food (7012C LM-485 mice/rat diet of sterilizing, Harlan Teklad, Madison, WI) and water.The animal agreement obtains the InstitutionalAnimal Care and Use Committee 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 orchiectomy (ORX) animal in addition.Also estimated the regeneration of compound III in chronic (9 days) ORX rat.
Described chemical compound weighed and be dissolved in 10% usefulness PEG 300 (Acros Organics NJ) among Xi Shi the DMSO (Fisher), is used to prepare proper dosage concentration.Raise 2-3 animal in each cage.The random assortment of complete sum ORX animal is become 7 groups, form by 4-5 animal for every group.Matched 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 with 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/ 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.After the dosage regimens on the 14th with Animal Anesthesia (ketamine/dimelazine (xyalzine), 87: 13mg/kg) put to death, and the record body weight.In addition, take out prostate siphonal lobe, seminal vesicle and levator ani m., weigh separately, carry out standardization, represent with the percentage ratio of complete matched group according to body weight.Use more independent dosage group and the complete matched 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 levator ani m. weight is as estimating anabolic measuring.Collect blood from ventral aorta, 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 Assay and AnalysisCore 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 handled is respectively 111% ± 21%, 88% ± 15%, 77% ± 17%, 71% ± 16%, 71% ± 10% and 87% ± 13% (Fig. 5) of complete matched group.Similarly, give dosage 0.01,0.03,0.1,0.3,0.75 and 1mg/ after day, seminal vesicle weight is reduced to 94% ± 9%, 77% ± 11%, 80% ± 9%, 73% ± 12%, 77% ± 10% and 88% ± 14% of complete matched group respectively.But in all dosage groups when comparing with complete contrast, the levator ani m. weight of observing the sham-operation animal significantly increases.Corresponding to 0.01,0.03,0.1,0.3,0.75 and 1mg/ daily dose group, levator ani m. 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 reduced to 5% ± 1% of complete contrast in the ORX of vehicle treated contrast.At dosage is 0.01,0.03,0.1,0.3,0.75 and 1.0mg/ during day, and it is 8% ± 2%, 20% ± 5%, 51% ± 19%, 56% ± 9%, 80% ± 28% and 74% ± 12.5% of complete contrast that compound III keeps weight of prostate respectively.In the castrating contrast, seminal vesicle weight is reduced to 13% ± 2% of complete matched 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/ 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, levator ani m. weight is reduced to 55% ± 7% of complete matched group.In the levator ani m. of the animal that compound III is handled, we observe anabolic action.Compound III keeps levator ani m. weight fully at dosage＞0.1mg/ during day.With observed comparing in complete contrast, dosage＞0.1mg/ day causes levator ani m. weight significantly to increase.For 0.01,0.03,0.1,0.3,0.75 and 1.0mg/ daily dose group, in the percentage ratio of complete matched group, levator ani m. 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 determined by the nonlinear regression analysis among the WinNonlin , and is provided in Fig. 7.The E of prostate, seminal vesicle and levator ani m. MaxValue is respectively 83% ± 25%, 85% ± 11% and 13 1% ± 2%.The ED of prostate, seminal vesicle and levator ani m. 50Be respectively 0.09 ± 0.07,0.17 ± 0.05 and 0.02 ± 0.01mg/ day.
Serum hormone is analyzed
Serum Lh of animal and FSH data provide in table 1.LH all reduces in the dose dependent mode in the complete sum neuter.Give dosage＞0.1mg/ after day, the LH level is lower than quantitative limit (0.07mg/ day).The 0.1mg/ daily dose makes the LH level get back to level seen in the complete matched group in the ORX animal.Also observe similar effect for FSH.In intact animal, 0.75 and the 1mg/ daily dose observe the FSH level and significantly reduce.In the ORX animal, observe the horizontal dose dependent of FSH and reduce.In the ORX animal, the dosage of compound III＞0.1mg/ day makes the FSH level get back to complete control level.
Lutropin Follicle stimulating hormone
Compound III (mg/ day) Complete (ng/ml) ORX (ng/ml) Complete (ng/ml) ORX (ng/ml)
Carrier 0.281±0.126 b 9.66±1.13 a 6.40±1.58 b 43.45±4.97 a
0.01 0.195±0.106 b 8.45±2.44 a 5.81±0.31 b 36.23±7.75 a
0.03 0.176±0.092 b 4.71±1.72 a，b 5.74±0.78 b 40.15±3.33 a
0.1 0.177±0.058 b 0.778±0.479 a 6.60±1.06 b 20.69±3.52 a，b
0.3 ＜LOQ ＜LOQ 5.32±1.80 a，b 8.73±2.25 b
0.75 ＜LOQ ＜LOQ 4.30±0.62 a，b 7.19±1.11 b
1 ＜LOQ ＜LOQ 4.38±0.42 a，b 6.33±0.70 b
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 and seminal vesicle weight.For 0.01,0.03,0.1,0.3,0.75 and 1.0mg/ daily dose group, prostate returns to 9% ± 3%, 11% ± 3%, 23% ± 5%, 50% ± 13%, 62% ± 12% and 71% ± 5% of complete contrast respectively, and seminal vesicle regain one's integrity the contrast 7% ± 1%, 9% ± 1%, 23% ± 8%, 49% ± 5%, 67% ± 12% and 67% ± 11%.Compound III during day, is recovered levator ani m. weight at dosage＞0.1mg/ fully.Corresponding to dosage 0.01,0.03,0.1,0.3,0.75 and 1.0mg/ day, levator ani m. weight returns to 56% ± 7%, 82% ± 9%, 103% ± 11%, 113% ± 1 1%, 121% ± 7% and 120% ± 7% respectively.The result provides with chart in Fig. 8.The E of each tissue MaxAnd ED 50Value is determined by the nonlinear regression analysis among the WinNonlin , and is provided in Fig. 9.The E of prostate, seminal vesicle and levator ani m. MaxValue is respectively 75% ± 8%, 73% ± 3% and 126% ± 4%.The ED of prostate, seminal vesicle and levator ani m. 50Be respectively 0.22 ± 0.05,0.21 ± 0.02 and 0.013 ± 0.01mg/ day.
Embodiment 4:
The pharmacokinetics feature of new oral anabolism SARM compound III:
Analysis first in the healthy male volunteers
Material and method
With the randomized, double-blind research design maximum one group of 12 healthy male volunteers is carried out administration with each dosage level (9 activity, 3 placebo).Recruit 8 groups (age 18-45 years), the once single oral dose of every group of received, described dosage is corresponding to 1,3,10,30 and 100mg compound III in solution (or isopyknic PEG 300 placebo) or 3 or 30mg compound III in the test capsule.Studied the influence of micronization (being that particle diameter reduces) with the form of 30mg solid oral dosage form to the pharmacokinetics of compound III.The sample that is used for the evaluation of female medicine pharmacokinetics 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 all gageable compound III plasma concentration of an acquisition time point (72 hours) (Figure 10-12) to the last.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(Fig. 13 and 14).For 1-100mg solution and 3mg capsule, eventually to eliminate the half-life 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 half-life, compares with dosage with other dosage form, and the non-micronization capsule of 30mg shows the long half-lift and the minimum clearing rate.Non-micronization capsule of 3mg and solution have equal bioavailability, but improve oral administration biaavailability (p＜0.5) (Figure 12) at higher dosage (30mg) micronization.As indicated in successive second peak in eliminating mutually 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 pumps (2002 type) available from Alza Corp. (Palo Alto, CA).
The SARM of test will comprise as follows:
Figure A20058001846800541
With
The specific activity of their activity and following chemical compound is:
Figure A20058001846800552
Figure A20058001846800553
With
Figure A20058001846800554
Research design: with the Sprague-Dawley rat random packet of immature heavy 90-100mg, every group of at least 5 animals.In beginning a day before the drug treating, from cage, take out animal is single, weigh and give ketamine/dimelazine (87/13mg/kg by intraperitoneal; About 1mL/kg) anesthesia.When suitable anesthesia (promptly to pinching not reaction of toe), for the purpose confirmed gives labelling with the ear of animal.Then animal is placed on the sterile pad, cleans its abdominal part and scrotum with povidone iodine and 70% ethanol.Cut the taking-up testis via middle line of scrotum, aseptic stitching is used for ligation testis top tissue, each testis of surgical removal then.Close the surgical wound position with aseptic rustless steel wound clips, and clean this position with povidone iodine.Allow animal on sterile pad, revive (until standing), then they are put back in the cage.
After 20 hours, animal is anaesthetized again, and will contain under Alzet osmotic pumps (2002 type) percutaneous of SARM chemical compound and be placed on the omoplate district with ketamine/dimelazine.Osmotic pumps contains the suitable medicine (as described in embodiment 3) that is dissolved in the Liquid Macrogol (PEG 300).Fill osmotic pumps 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 ventral aorta venipuncture, and carry out the whole blood cell analysis.A part of blood sample is placed in the separator tube centrifugal 1 minute with 12000g.Remove plasma layer and frozen down at-20 ℃.Take out prostate siphonal lobe, seminal vesicle, levator ani m., 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 standardization with body weight, carries out the statistical significant difference analysis by single factor ANOVA.The weight of prostate and seminal vesicle is urged male active index as estimating, and levator ani m. weight is used to estimate anabolic activity.
Be used as the positive controls of anabolism and short male effect with the Testosterone Propionate (TP) that increases dosage.Thereby the effect and the TP of specific compound can be compared.
The weight that is expected at prostate, seminal vesicle and levator ani m. in the rat of castrating, vehicle treated significantly reduces because of the cut-out that the endogenous androgen 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 levator ani m. in the dose dependent mode.The influence of SARM to the weight of neuter prostate, seminal vesicle and levator ani m. will be estimated comparatively.Aspect the weight that increases prostate and seminal vesicle, show low usefulness and intrinsic activity, and increasing the chemical compound that shows higher performance and intrinsic activity aspect the weight of levator ani m., to be considered to short male a little less than, but have anabolic activity, representative will be used for the treatment of carcinoma of prostate for example or be used for the treatment of the chemical compound that relevant side effect is treated in and carcinoma of prostate treatment at present as androgen-deprivation.
Embodiment 6
SARM is to the reduction of cholesterol level
Material and method
100 Spargue Dawley rats (50 male and 50 female) are divided into 5 groups (every group every kind sex n=10), and its representative has only carrier, and (PEG 300: 40%Cavasol [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 compound III once a day 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 handle to obtain serum.Use automatic laboratory determination method to measure serum total cholesterol level.
The result
Male and serum cholesterol value female rats in having only 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 dose 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 T-CHOL reduces, and wherein male and femalely is respectively 63 ± 17.4 and 74 ± 14.2mg/L.Though noticing in maximum dose level group (100mg/kg/ day) has slight bigger 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, by diagnosis hematology test with dock subject animal visual inspection and measure, compacting lutropin (LH) or follicle stimulating hormone (FSH) that will be described in above embodiment 4.
Although this paper is illustration and described some feature of the present invention, many modifications will take place, 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 (46)

1.一种由式(I)的结构代表的选择性雄激素受体调节剂(SARM)化合物或其前药、类似物、异构体、代谢物、衍生物、药学可接受的盐、药品、多晶型物、晶体、不纯物、N-氧化物、水合物或其任意组合：1. A selective androgen receptor modulator (SARM) compound represented by a structure of formula (I) or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, medicine , polymorphs, crystals, impurities, N-oxides, hydrates, or any combination thereof:
Figure A2005800184680002C1
Figure A2005800184680002C1
 其中X为O；where X is O; Z为NO2、CN、COR或CONHR；Z is NO 2 , CN, COR or CONHR; Y为I、CF3、Br、Cl、F或Sn(R)3；Y is I, CF 3 , Br, Cl, F or Sn(R) 3 ; Q为CN；Q is CN; T为OH、OR、-NHCOCH3、NHCOR或OC(O)R；T is OH, OR, -NHCOCH 3 , NHCOR or OC(O)R; R为烷基、卤代烷基、二卤代烷基、三卤代烷基、CH2F、CHF2、CF3、CF2CF3、芳基、苯基、卤素、烯基或OH；且R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F , CHF2 , CF3 , CF2CF3 , aryl, phenyl, halogen, alkenyl, or OH; and R1为CH3、CH2F、CHF2、CF3、CH2CH3或CF2CF3。R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 or CF 2 CF 3 . 2.权利要求1的SARM化合物，其中所述SARM化合物由式(II)的结构代表：2. The SARM compound of claim 1, wherein said SARM compound is represented by the structure of formula (II): 其中X为O；where X is O; Z为NO2、CN、COR或CONHR；Z is NO 2 , CN, COR or CONHR; Y为I、CF3、Br、Cl、F或Sn(R)3；Y is I, CF 3 , Br, Cl, F or Sn(R) 3 ; R为烷基或OH；且R is alkyl or OH; and Q为CN。Q is CN. 3.一种由式(III)的结构代表的选择性雄激素受体调节剂(SARM)化合物或其前药、类似物、异构体、代谢物、衍生物、药学可接受的盐、药品、多晶型物、晶体、不纯物、N-氧化物、水合物或其任意组合：3. A selective androgen receptor modulator (SARM) compound represented by a structure of formula (III) or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, medicine , polymorphs, crystals, impurities, N-oxides, hydrates, or any combination thereof: 4.一种由式(IV)的结构代表的选择性雄激素受体调节剂(SARM)化合物或其前药、类似物、异构体、代谢物、衍生物、药学可接受的盐、药品、多晶型物、晶体、不纯物、N-氧化物、水合物或其任意组合：4. A selective androgen receptor modulator (SARM) compound represented by the structure of formula (IV) or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, medicine , polymorphs, crystals, impurities, N-oxides, hydrates, or any combination thereof:
Figure A2005800184680003C2
Figure A2005800184680003C2
 其中X为O；where X is O; T为OH、OR、NHCOCH3、NHCOR或OC(O)R；T is OH, OR, NHCOCH 3 , NHCOR or OC(O)R; Z为H、烷基、NO2、CN、COOH、COR、NHCOR或CONHR；Z is H, alkyl, NO2 , CN, COOH, COR, NHCOR or CONHR; Y为H、烷基、CF3、卤素、羟基-烷基或烷基醛；Y is H, alkyl, CF3 , halogen, hydroxy-alkyl or alkylaldehyde; A是选自以下的基团：A is a group selected from:
Figure A2005800184680004C1
Figure A2005800184680004C1
 其中in R2、R3、R4、R5、R6独立地为H、卤素、CN、NO2、NHCOCF3；R 2 , R 3 , R 4 , R 5 , R 6 are independently H, halogen, CN, NO 2 , NHCOCF 3 ; R为烷基、卤代烷基、二卤代烷基、三卤代烷基、CH2F、CHF2、CF3、CF2CF3、芳基、苯基、卤素、烯基或OH；且R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F , CHF2 , CF3 , CF2CF3 , aryl, phenyl, halogen, alkenyl, or OH; and R1为CH3、CH2F、CHF2、CF3、CH2CH3或CF2CF3。R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 or CF 2 CF 3 . 5.权利要求4的SARM化合物，其中X为O。5. The SARM compound of claim 4, wherein X is O. 6.权利要求4的SARM化合物，其中T为OH。6. The SARM compound of claim 4, wherein T is OH. 7.权利要求4的SARM化合物，其中R1为CH3。7. The SARM compound of claim 4, wherein R1 is CH3 . 8.权利要求4的SARM化合物，其中Z为NO2。8. The SARM compound of claim 4, wherein Z is NO2 . 9.权利要求4的SARM化合物，其中Z为CN。9. The SARM compound of claim 4, wherein Z is CN. 10.权利要求4的SARM化合物，其中R2、R3、R5、R6为H，而R4为NHCOCF3。10. The SARM compound of claim 4, wherein R2 , R3 , R5 , R6 are H and R4 is NHCOCF3 . 11.权利要求4的SARM化合物，其中R2、R3、R5、R6为H，而R4为F。11. The SARM compound of claim 4, wherein R2 , R3 , R5 , R6 are H and R4 is F. 12.权利要求4的SARM化合物，其中R2、R3、R5、R6为H。12. The SARM compound of claim 4, wherein R2 , R3 , R5 , R6 are H. 13.权利要求4的SARM化合物，其中R2、R3、R5、R6为F，而R4为NHCOCF3。13. The SARM compound of claim 4, wherein R2 , R3 , R5 , R6 are F and R4 is NHCOCF3 . 14.权利要求4的SARM化合物，其中R2、R3、R5、R6为F。14. The SARM compound of claim 4, wherein R2 , R3 , R5 , R6 are F. 15.权利要求14的SARM化合物，其中R2、R3、R4、R5和R6为F。15. The SARM compound of claim 14, wherein R2 , R3 , R4 , R5 and R6 are F. 16.权利要求4的SARM化合物，其中Z在对位。16. The SARM compound of claim 4, wherein Z is in the para position. 17.权利要求4的SARM化合物，其中Y在间位。17. The SARM compound of claim 4, wherein Y is in the meta position. 18.一种组合物，其含有权利要求1、2、3或4的SARM化合物和合适的载体或稀释剂。18. A composition comprising a SARM compound according to claim 1, 2, 3 or 4 and a suitable carrier or diluent. 19.权利要求18的组合物，其还含有阿仑膦酸盐。19. The composition of claim 18, further comprising alendronate. 20.权利要求1、2、3或4的SARM化合物或含有其的组合物在治疗患有骨相关病症个体中的应用。20. Use of a SARM compound of claim 1 , 2, 3 or 4, or a composition containing the same, for the treatment of an individual suffering from a bone-related disorder. 21.权利要求16的应用，其中所述骨相关病症是骨质疏松、骨质减少、骨吸收增加、骨折、骨脆弱、骨矿密度(BMD)降低或其任意组合。21. The use of claim 16, wherein said bone-related disorder is osteoporosis, osteopenia, increased bone resorption, bone fracture, bone fragility, decreased bone mineral density (BMD), or any combination thereof. 22.权利要求16的应用，其中所述组合物还含有阿仑膦酸盐。22. The use of claim 16, wherein said composition further comprises alendronate. 23.权利要求1、2、3或4的SARM化合物或含有其的组合物在增加个体骨强度或骨量或者促进个体骨形成中的应用。23. Use of a SARM compound according to claim 1 , 2, 3 or 4, or a composition containing the same, for increasing bone strength or bone mass or promoting bone formation in a subject. 24.权利要求23的应用，其中所述组合物还含有阿仑膦酸盐。24. The use of claim 23, wherein said composition further comprises alendronate. 25.权利要求23的应用，其中所述骨是皮质骨。25. The use of claim 23, wherein said bone is cortical bone. 26.权利要求23的应用，其中所述骨是小梁骨或松质骨。26. The use of claim 23, wherein said bone is trabecular bone or cancellous bone. 27.权利要求23的应用，其中所述SARM化合物刺激或增强成骨细胞生成。27. The use of claim 23, wherein said SARM compound stimulates or enhances osteoblastogenesis. 28.权利要求23的应用，其中所述SARM化合物抑制破骨细胞增殖。28. The use of claim 23, wherein said SARM compound inhibits osteoclast proliferation. 29.权利要求23的应用，其中所述个体患有肌肉减少症或恶病质。29. The use of claim 23, wherein said individual suffers from sarcopenia or cachexia. 30.权利要求1、2、3或4的SARM化合物或含有其的组合物在干预或预防骨质疏松或骨质减少中的应用。30. Use of a SARM compound according to claim 1 , 2, 3 or 4 or a composition containing it for the intervention or prevention of osteoporosis or osteopenia. 31.权利要求25的应用，其中所述个体患有骨质疏松。31. The use of claim 25, wherein said individual suffers from osteoporosis. 32.权利要求25的应用，其中所述骨质疏松是激素引起的。32. The use of claim 25, wherein said osteoporosis is caused by hormones. 33.权利要求1、2、3或4的SARM化合物或含有其的组合物在治疗、预防、压制、抑制个体肌肉消瘦症或降低个体肌肉消瘦症的发生率中的应用。33. Use of the SARM compound of claim 1, 2, 3 or 4 or a composition containing the same for treating, preventing, suppressing, inhibiting or reducing the incidence of muscle wasting in an individual. 34.权利要求33的应用，其中所述肌肉消瘦症由病理、病痛、疾病或病症引起。34. The use of claim 33, wherein said muscular wasting is caused by a pathology, ailment, disease or condition. 35.权利要求34的应用，其中所述病理、病痛、疾病或病症是神经性、感染性、慢性或遗传性的。35. The use of claim 34, wherein the pathology, ailment, disease or condition is neurological, infectious, chronic or genetic. 36.权利要求35的应用，其中所述病理、病痛、疾病或病症是肌营养不良、肌萎缩、X连锁脊延髓肌萎缩(SBMA)、恶病质、营养不良、麻风、糖尿病、肾病、慢性阻塞性肺病(COPD)、癌症、末期肾衰、肌肉减少症、肺气肿、骨软化症、HIV感染、AIDS、充血性心力衰竭(CHF)或心肌病。36. The use of claim 35, wherein said pathology, ailment, disease or condition is muscular dystrophy, muscular atrophy, X-linked spinobulbar muscular atrophy (SBMA), cachexia, malnutrition, leprosy, diabetes, nephropathy, chronic obstructive Lung disease (COPD), cancer, end-stage renal failure, sarcopenia, emphysema, osteomalacia, HIV infection, AIDS, congestive heart failure (CHF), or cardiomyopathy. 37.权利要求33的应用，其中所述肌肉消瘦症是年龄相关的肌肉消瘦症；废用性功能退化相关的肌肉消瘦症；或所述肌肉消瘦症由慢性下背疼痛；烧伤；中枢神经系统(CNS)损伤或损害；周围神经损伤或损害；脊髓损伤或损害；化学损伤或损害；或者酒精中毒引起。37. The use of claim 33, wherein said muscular wasting is age-related muscular wasting; disuse-related degeneration of muscular wasting; or said muscular wasting is caused by chronic lower back pain; burns; central nervous system (CNS) injury or damage; peripheral nerve injury or damage; spinal cord injury or damage; chemical injury or damage; or alcohol intoxication. 38.权利要求33的应用，其中所述组合物以液体形式经静脉内、动脉内或肌内给予；或以小丸形式经皮下植入所述个体中；以液体或固体形式口服给予；以液体或固体形式舌下给予；或者通过将所述药物组合物施用于所述个体的粘膜表面而局部给予。38. The use of claim 33, wherein said composition is administered intravenously, intraarterially or intramuscularly in liquid form; or implanted subcutaneously in said individual in pellet form; orally administered in liquid or solid form; in liquid form Either sublingually in solid form; or topically by applying the pharmaceutical composition to a mucosal surface of the individual. 39.权利要求35的应用，其中所述组合物是丸剂、片剂、胶囊剂、溶液剂、混悬剂、乳剂、酏剂、凝胶剂、乳膏、栓剂或肠胃外制剂。39. The use of claim 35, wherein said composition is a pill, tablet, capsule, solution, suspension, emulsion, elixir, gel, cream, suppository or parenteral formulation. 40.权利要求1、2、3或4的SARM化合物或含有其的组合物在增加个体肌肉行为表现、肌肉大小、肌力或其任意组合中的应用。40. Use of the SARM compound of claim 1, 2, 3 or 4, or a composition containing the same, for increasing muscle performance, muscle size, muscle strength, or any combination thereof in an individual. 41.权利要求1、2、3或4的SARM化合物或含有其的组合物在治疗个体代谢综合征相关的肥胖或糖尿病中的应用。41. Use of a SARM compound of claim 1 , 2, 3 or 4, or a composition comprising the same, for the treatment of obesity or diabetes associated with metabolic syndrome in an individual. 42.权利要求41的应用，其中所述个体患有激素失衡、紊乱或疾病。42. The use of claim 41, wherein said individual suffers from a hormonal imbalance, disorder or disease. 43.权利要求42的应用，其中所述个体处于绝经期。43. The use of claim 42, wherein said individual is in menopause. 44.权利要求42的应用，其中所述SARM增加个体的瘦重。44. The use of claim 42, wherein said SARM increases lean body mass in the individual. 45.权利要求1、2、3或4的SARM化合物或含有其的组合物在促进或加速手术操作后恢复中的应用。45. Use of a SARM compound according to claim 1, 2, 3 or 4, or a composition containing the same, for promoting or accelerating recovery after a surgical procedure. 46.权利要求1、2、3或4的SARM化合物或含有其的组合物在促进或压制男性个体精子发生中的应用。46. Use of a SARM compound according to claim 1, 2, 3 or 4, or a composition containing the same, for promoting or suppressing spermatogenesis in a male individual.
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