CN1736981A - 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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CN1736981A
CN1736981A CN 200510067495 CN200510067495A CN1736981A CN 1736981 A CN1736981 A CN 1736981A CN 200510067495 CN200510067495 CN 200510067495 CN 200510067495 A CN200510067495 A CN 200510067495A CN 1736981 A CN1736981 A CN 1736981A
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sarm
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androgen receptor
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詹姆斯·多尔顿
杜安·D·米勒
尹东华
何雅丽
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University of Tennessee Research Foundation
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Abstract

This invention provides a novel class of androgen receptor targeting agents (ARTA). The agents define a new subclass of compounds which are tissue-selective androgen receptor modulators (SARM), which are useful for oral testosterone replacement therapy, male contraception, maintaining sexual desire in women, treating prostate cancer and imaging prostate cancer. These agents have an unexpected in-vivo activity for an androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor. These agents may be active alone or in combination with progestins or estrogens. The invention further provides a novel class of non-steroidal agonist compounds. The invention further provides compositions containing the selective androgen modulator compounds or the non-steroidal agonist compounds and methods of binding an androgen receptor, modulating spermatogenesis, treating and imaging prostate cancer, and providing hormonal therapy for androgen-dependent conditions.

Description

SARM and using method thereof
The application submits to August 23 calendar year 2001, and denomination of invention is divided an application for the Chinese patent application 01817889.8 of " SARM and using method thereof ".
Technical field
The present invention relates to new class tissue selective androgen receptor target agent (ARTA), they demonstrate the short male and anabolic activity of the on-steroidal part of androgen receptor.The target agent defines the new subclass compound that those are tissue selective androgen receptor conditioning agents (SARM), they for male hormone therapy such as oral testosterone replacement therapy, male contraception, keep women's sexual desire, treatment prostate cancer and prostate cancer imaging is useful.Also these reagent are given the experimenter with treatment Sarcopenia (sarcopenia), hyposexuality, osteoporosis, erythropoiesis and fertility.The target agent can be used separately or unite use with progesterone or oestrogenic hormon.
Background technology
Androgen receptor (" AR ") is a part activated transcription regulatory protein, and it mediates male sex's sexual development and function by its endogenous androgenic activity.Male sex hormone is commonly called androgen.Yet in female pathology and reproduction, male sex hormone is also brought into play keying action.Male sex hormone is produced in vivo by testis and adrenal cortex, perhaps synthetic steroid in the laboratory.Androgenic steroids plays an important role in many physiological processs, described process comprises the growth of male sex characteristics (distributing as muscle and bone amount (bone mass), prostate gland growth, spermatogeny and male sex's hair) and keeps (Matsumoto, Endocrinol.Met.Clin.N.Am.23:857-75 (1994).Endogenous steroid male sex hormone comprises testosterone and dihydrotestosterone (" DHT ").Testosterone is the main steroid by testicular secretion, and is the main circulation male sex hormone of finding in male blood plasma.In many peripheral tissues, testosterone is converted 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 male sex hormone comprises the ester of testosterone, as cipionate, propionic ester, phenylpropionic acid ester, cyclopentanepropanoiacid acid ester, isocarporate, heptanoate and decylate, and other synthetic androgen such as 7-methylnortestosterone (" MENT ") and acetic ester thereof) (people such as Sundaram, " 7 Alpha-Methyl-Nortestosterone (MENT): The Optimal Androgen For Male Contraception; " Ann.Med., 25:199-205 (1993) (" Sundaram ")).Owing to relate to AR in male sex's sexual development and function, AR is likely the target of the hormone replacement therapy that realizes male contraception or other form.AR also regulates femal sexual function (being sexual desire), bone forming and erythropoiesis.
The social consciousness of worldwide population growth and birth control has encouraged people to carry out big quantity research at contraception.Contraception under any circumstance all is a difficult problem.It is full of culture and society branding, religion involve, and the most definite be great healthy effect.When theme concentrated on male contraception, these situations only can more be aggravated.Although suitable contraceptive device is arranged, in history, society expects that the women shoulders the responsibility of contraception decision and its consequence.Though for the health of sexually transmitted disease (STD) is considered to make the male sex have recognized the need to form safe and responsible sexual custom more that the women still usually bears the pressure that contraception is selected.The women has many selections, from temporary transient mechanical implement such as sponge and barrier film to temporary transient chemical utensil such as spermicide.The women also has the more persistent selection that arranged by they, as if the physics utensil of IUDs and Diaphragm contraceptive and so on, and such as the more persistent chemotherapy of oral contraceptive and hypodermic implant.Yet up to now, the only selection of man comprises uses condom or vasotomy., because minimizing property susceptibility, disruptive is spontaneous and cause pregnant obvious possibility because of breaking or misapply, so, many man's disapproves use condoms.Vasotomy is also agreed with.If the man has the long-acting method that need not prolusion before the contraceptive device more easily, particularly sexual behaviour at once, these class methods can increase the man bears more responsibilities to contraception possibility significantly.
In this regard, give androgen (for example testosterone and derivative thereof) and demonstrated special hope, this is because these compounds have suppresses gonad-stimulating hormone and substitute androgenic association property (people such as Steinberger, " Effect of Chronic Administration ofTestosterone Enanthate on Sperm Production and Plasma Testosterone; Follicle Stimulating Hormone; and Luteinizing Hormone Levels:APreliminary Evaluation of a Possible Male Contraceptive ", Fertility andSterility 28:1320-28 (1977)).Giving the high dosage testosterone for a long time eliminates sperm generation (no sperm) fully or makes oligospermia to the utmost point low-level (oligospermia).The degree that suppresses for the sterile required spermatogeny of generation does not know for sure.Yet, recently the report of the World Health Organization shows, intramuscularly testosterone heptanoate causes no sperm or serious oligospermia (be every milliliter less than 3,000,000 sperms) and sterile (WorldHealth Organization Task Force on Methods Ar Regulation of MaleFertility in 98% the man who receives treatment weekly, " Contraceptive Efficacy of Testosterone-Induced Azoospermiaand Oligospermia in Normal Men, " Fertilily and Sterility 65:821-29 (1996)).
Develop absorbed slowlyer various testosterone esters after the intramuscularly, therefore, caused stronger short male function.In these esters, the testosterone heptanoate is most widely used.Though it is valuable that the testosterone heptanoate is used in foundation aspect the feasibility of hormone drug of male contraception, but it has some defectives, comprise need inject weekly with intramuscularly after the testosterone that occurs immediately excusing from death reason peak level have (a Wu, " Effects ofTestosterone Enanthate in Normal Men:Experience From a Multicenter Contraceptive Efficacy Study, " Fertilityand Sterility 65:626-36 (1996)).
In conjunction with AR and serve as male sex hormone (for example testosterone heptanoate) or serve as the steroid part of androgen antagonist (for example cyproterone acetate) for many years known, and use (Wu 1988) clinically.Although the on-steroidal androgen antagonist is used for the hormonal dependent prostate cancer clinically,, still there is not the androgenic report of on-steroidal.Therefore, the research to male contraceptive pill mainly concentrates on the sterid.
Summary of the invention
The invention provides new class tissue selective androgen receptor target agent (ARTA).The target agent defines the new subclass compound that those are tissue selective androgen receptor conditioning agents (SARM), they for oral testosterone replacement therapy, male contraception, to keep women's sexual desire, osteoporosis, treatment prostate cancer and prostate cancer imaging useful.These reagent have the activity in vivo of short male and anabolic activity of on-steroidal part of the androgen receptor of inexpectancy and tissue selectivity.These reagent selectivity ground serves as partial agonist in some tissues, and serves as full agonist in other tissue, provides new and unexpected initiation tissue selectivity to urge the means of male or anabolic action.These reagent may promptly have activity separately, perhaps have activity with the associating of progesterone or oestrogenic hormon.The present invention further provides novel class of non-steroidal agonist compounds.The present invention further provides the composition that comprises selective androgen conditioning agent compound or non-steroidal agonist compounds, provide in conjunction with AR, regulate spermatogeny, bone forming and/or absorption again, prostate cancer therapy and imaging method, and be provided for the hormonotherapy of the androgen-dependent patient's condition.
The present invention relates to the SARM compound, it has short male and anabolic activity in the body of on-steroidal part of androgen receptor of tissue selectivity, and this SARM compound is represented by formula I structure:
Figure A20051006749500101
Wherein X is O, CH 2, NH, Se, PR or NR;
Z is NO 2, CN, COR, COOH or CONHR;
Y is I, CF 3, Br, Cl or SnR 3
Q is alkyl, halogen, NR 2, NHCOCH 3, NHCOCF 3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3, NHCSCF 3, NHCSR, NHSO 2CH 3, NHSO 2R, OR, COR, OCOR, OSO 2R, SO 2R or SR,
Wherein R is alkyl, aryl, hydroxyl, C 1-C 4Alkyl, C 1-C 4Alkylhalide group, phenyl, halogen, alkenyl or hydroxyl;
Perhaps Q be the condensed ring system that represents by structure A, B or C with the phenyl ring that it was connected:
Figure A20051006749500111
R 1Be CH 3, CF 3, CH 2CH 3Or CF 2CF 3And
T be OH, OR ,-NHCOCH 3Or NHCOR, wherein R is C 1-C 4Alkyl, C 1-C 4Alkylhalide group, phenyl, halogen, alkenyl or hydroxyl.
In one embodiment, Q is in contraposition.In another embodiment, X is O.In another embodiment, Q is in contraposition and X is O.In another embodiment, Q is contraposition alkyl, halogen, NR 2, NHCOCH 3, NHCOCF 3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3, NHCSCF 3, NHCSR, NHSO 2CH 3, NHSO 2R, OR, COR, OCOR, OSO 2R, SO 2R or SR, wherein R is alkyl, aryl, hydroxyl, C 1-C 4Alkyl, C 1-C 4Alkylhalide group, phenyl, halogen, alkenyl or hydroxyl.
The present invention relates to the SARM compound, it has the interior short male and anabolic activity of body of the on-steroidal part of androgen receptor, and this SARM compound is represented by formula II structure:
Figure A20051006749500112
Wherein X is O, CH 2, NH, Se, PR or NR;
Z is hydrogen bond receptor, NO 2, CN, COR, CONHR;
Y is fat-soluble group, I, CF 3, Br, Cl, SnR 3
R is alkyl or aryl or OH; And
Q be acetylaminohydroxyphenylarsonic acid, trifluoroacetamido-, alkylamine, ether, alkyl, N-alkylsulfonyl, O-alkylsulfonyl, alkyl sulphonyl, carbonyl or ketone.
The invention still further relates to the SARM compound, it has the interior short male and anabolic activity of body of the on-steroidal part of androgen receptor, and this SARM compound is represented by the formula III structure:
Figure A20051006749500121
Wherein X is O, CH 2, NH, Se, PR or NR;
Z is NO 2, CN, COR or CONHR;
Y is I, CF 3, Br, Cl or SnR 3
R is alkyl or aryl or OH; And
Q is kharophen or trifluoroacetamido.
The invention still further relates to the SARM compound, it has short male and anabolic activity in the body of on-steroidal part of androgen receptor of tissue selectivity, and this SARM compound is represented by formula IV structure:
Figure A20051006749500122
The invention still further relates to the SARM compound, it has short male and anabolic activity in the body of on-steroidal part of androgen receptor of tissue selectivity, and this SARM compound is represented by formula V structure:
The invention still further relates to the SARM compound, it has short male and anabolic activity in the body of on-steroidal part of androgen receptor of tissue selectivity, and this SARM compound is represented by formula VI structure:
The invention still further relates to the SARM compound, it has for short male and anabolic activity in the body of the on-steroidal part of the androgen receptor of tissue selectivity, and this SARM compound is represented by formula VII structure:
The invention still further relates to SARM compound and androgen receptor bonded method, it is included in and makes under SARM compound and the effective bonded condition of androgen receptor, and androgen receptor is contacted with the SARM compound.In one embodiment, compound is a Compound I.In another embodiment, compound is Compound I I.In another embodiment, compound is a compound III.In another embodiment, compound is a compound IV.In another embodiment, compound is compound V.In another embodiment, compound is a compound VI.In another embodiment, compound is compound VI I.In another embodiment, compound is a compound VIII.
The invention still further relates to the spermatogenetic method of experimenter of regulating, it is included in effective increase or reduces under the condition of sperm generation, and experimenter's androgen receptor is contacted with the SARM compound.In one embodiment, compound is a Compound I.In another embodiment, compound is Compound I I.In another embodiment, compound is a compound III.In another embodiment, compound is a compound IV.In another embodiment, compound is compound V.In another embodiment, compound is a compound VI.In another embodiment, compound is compound VI I.In another embodiment, compound is a compound VIII.
The invention still further relates to methods of hormonal treatment, be included in and make SARM compound and androgen receptor effectively combine and realize under the condition of change of the androgen-dependent patient's condition experimenter's androgen receptor to be contacted with the SARM compound.In one embodiment, compound is a Compound I.In another embodiment, compound is Compound I I.In another embodiment, compound is a compound III.In another embodiment, compound is a compound IV.In another embodiment, compound is compound V.In another embodiment, compound is a compound VI.In another embodiment, compound is compound VI I.In another embodiment, compound is a compound VIII.
The invention still further relates to treatment and suffer from the experimenter's of hormone related conditions method, be included in and make SARM compound and androgen receptor effectively combine and realize under the condition of change of the androgen-dependent patient's condition experimenter's androgen receptor to be contacted with the SARM compound.In one embodiment, the SARM compound is optionally to male sex hormone or testosterone receptor.The invention still further relates to the method for orally give SARM compound.
The invention still further relates to treatment and suffer from the experimenter's of chronic amyotrophy morbid state method, be included in and make SARM compound and androgen receptor effectively combine and realize under the condition of change of the androgen-dependent patient's condition, the androgen receptor that makes described experimenter contacts with SARM compound as described herein.In one embodiment, the SARM compound is optionally to male sex hormone or testosterone receptor.The invention still further relates to the method for orally give SARM compound.In one embodiment, compound is a Compound I.In another embodiment, compound is Compound I I.In another embodiment, compound is a compound III.In another embodiment, compound is a compound IV.In another embodiment, compound is compound V.In another embodiment, compound is a compound VI.In another embodiment, compound is compound VI I.In another embodiment, compound is a compound VIII.
As defined herein, " chronic amyotrophy " be meant
The invention still further relates to treatment and suffer from the experimenter's of prostate cancer method, comprise the SARM compound that gives experimenter's significant quantity.In one embodiment, the SARM compound is optionally to male sex hormone or testosterone receptor.In one embodiment, compound is a Compound I.In another embodiment, compound is Compound I I.In another embodiment, compound is a compound III.In another embodiment, compound is a compound IV.In another embodiment, compound is compound V.In another embodiment, compound is a compound VI.In another embodiment, compound is compound VI I.In another embodiment, compound is a compound VIII.
The invention still further relates to composition and pharmaceutical composition, they comprise independent SARM and suitable carrier, thinner or salt, perhaps also comprise progesterone or oestrogenic hormon.In one embodiment, composition inclusion compound I.In another embodiment, compound is Compound I I.In another embodiment, compound is a compound III.In another embodiment, compound is a compound IV.In another embodiment, compound is compound V.In another embodiment, compound is a compound VI.In another embodiment, compound is compound VI I.In another embodiment, compound is a compound VIII.
The present invention relates to non-steroidal agonist compounds, this non-steroidal agonist compounds is represented by the structure of formula VIII:
Wherein X is O, CH 2, NH, Se, PR or NR;
R 1Be CH 3, CF 3, CH 2CH 3Or CF 2CF 3And
T be OH, OR ,-NHCOCH 3Or NHCOR, wherein R is C 1-C 4Alkyl, C 1-C 4Alkylhalide group, phenyl, halogen, alkenyl or hydroxyl;
A is 5 or 6 yuan of saturated, unsaturated or aromatic carbocyclic or heterocycles by following structure representative:
Figure A20051006749500161
Or
B is 5 or 6 yuan of saturated, unsaturated or aromatic carbocyclic or heterocycles by following structure representative:
Figure A20051006749500163
Or
Figure A20051006749500164
A wherein 1-A 11Each is C, O, S or N naturally;
B 1-B 11Each is C, O, S or N naturally;
Z is NO 2, CN, COOH, COR or CONHR;
Y is I, CF 3, Br, Cl or SnR 3And
Q 1And Q 2Be alkyl, halogen, NR independently of one another 2, NHCOCH 3, NHCOCF 3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3, NHCSCF 3, NHCSR, NHSO 2CH 3, NHSO 2R, OR, COR, OCOR, OSO 2R, SO 2R or SR, wherein R is C 1-C 4Alkyl, C 1-C 4Alkylhalide group, phenyl, halogen, alkenyl or hydroxyl.
The invention still further relates to composition and pharmaceutical composition, it comprises independent non-steroidal agonist compounds and suitable carrier, thinner or salt, perhaps also comprises progesterone or oestrogenic hormon.In one embodiment, compound is a Compound I.In another embodiment, compound is Compound I I.In another embodiment, compound is a compound III.In another embodiment, compound is a compound IV.In another embodiment, compound is compound V.In another embodiment, compound is a compound VI.In another embodiment, compound is compound VI I.In another embodiment, compound is a compound VIII.
The invention still further relates to non-steroidal agonist compounds and androgen receptor bonded method, it is included in and makes under non-steroidal agonist compounds and the effective bonded condition of androgen receptor, and androgen receptor is contacted with non-steroidal agonist compounds.In one embodiment, compound is a Compound I.In another embodiment, compound is Compound I I.In another embodiment, compound is a compound III.In another embodiment, compound is a compound IV.In another embodiment, compound is compound V.In another embodiment, compound is a compound VI.In another embodiment, compound is compound VI I.In another embodiment, compound is a compound VIII.
The invention still further relates to and regulate the spermatogenetic method of experimenter, be included under the condition of effective increase or the generation of minimizing sperm, experimenter's androgen receptor is contacted with non-steroidal agonist compounds.In one embodiment, compound is a Compound I.In another embodiment, compound is Compound I I.In another embodiment, compound is a compound III.In another embodiment, compound is a compound IV.In another embodiment, compound is compound V.In another embodiment, compound is a compound VI.In another embodiment, compound is compound VI I.In another embodiment, compound is a compound VIII.
The invention still further relates to methods of hormonal treatment, be included in and make non-steroidal agonist compounds and androgen receptor effectively combine and realize under the condition of change of the androgen-dependent patient's condition experimenter's androgen receptor to be contacted with the on-steroidal agonist.In one embodiment, compound is a Compound I.In another embodiment, compound is Compound I I.In another embodiment, compound is a compound III.In another embodiment, compound is a compound IV.In another embodiment, compound is compound V.In another embodiment, compound is a compound VI.In another embodiment, compound is compound VI I.In another embodiment, compound is a compound VIII.
The invention still further relates to treatment and suffer from the experimenter's of hormone related conditions method, be included in and make non-steroidal agonist compounds and androgen receptor effectively combine and realize under the condition of change of the androgen-dependent patient's condition described experimenter's androgen receptor to be contacted with non-steroidal agonist compounds.In one embodiment, non-steroidal agonist compounds is optionally to male sex hormone or testosterone receptor.The invention still further relates to the method for orally give non-steroidal agonist compounds.In one embodiment, compound is a Compound I.In another embodiment, compound is Compound I I.In another embodiment, compound is a compound III.In another embodiment, compound is a compound IV.In another embodiment, compound is compound V.In another embodiment, compound is a compound VI.In another embodiment, compound is compound VI I.In another embodiment, compound is a compound VIII.
The invention still further relates to treatment and suffer from the experimenter's of prostate cancer method, comprise the non-steroidal agonist compounds that gives experimenter's significant quantity.In one embodiment, non-steroidal agonist compounds is optionally to male sex hormone or testosterone receptor.In one embodiment, compound is a Compound I.In another embodiment, compound is Compound I I.In another embodiment, compound is a compound III.In another embodiment, compound is a compound IV.In another embodiment, compound is compound V.In another embodiment, compound is a compound VI.In another embodiment, compound is compound VI I.In another embodiment, compound is a compound VIII.
Another aspect of the present invention relates to the method for producing SARM of the present invention or on-steroidal androgen receptor agonist compound.In one embodiment, compound is a Compound I.In another embodiment, compound is Compound I I.In another embodiment, compound is a compound III.In another embodiment, compound is a compound IV.In another embodiment, compound is compound V.In another embodiment, compound is a compound VI.In another embodiment, compound is compound VI I.In another embodiment, compound is a compound VIII.
The invention further relates to the method for the existence of determining SARM compound of the present invention in the sample and/or non-steroidal agonist compounds.This method comprises the following steps: to obtain sample, and detects the compound in the sample, thereby determines the existence of compound in sample.In one embodiment, sample is serum, blood plasma, urine or saliva sample.In another embodiment, detect step and comprise the absorbancy of measuring compound.In one embodiment, compound is a Compound I.In another embodiment, compound is Compound I I.In another embodiment, compound is a compound III.In another embodiment, compound is a compound IV.In another embodiment, compound is compound V.In another embodiment, compound is a compound VI.In another embodiment, compound is compound VI I.In another embodiment, compound is a compound VIII.
New SARM compound and non-steroidal agonist compounds of the present invention, separately or as composition, various hormone related conditions for the treatment masculinity and femininity are useful, the described patient's condition such as hypogonadism, Sarcopenia, erythropoiesis, erection function, hyposexuality, osteoporosis and fertility.In addition, SARM compound and non-steroidal agonist compounds are for treatment prostate cancer, prostate cancer imaging with to keep the oral testosterone replacement therapy of women's sexual desire useful.These medicines can be united use separately or with progesterone or oestrogenic hormon.In one embodiment, compound is a Compound I.In another embodiment, compound is Compound I I.In another embodiment, compound is a compound III.In another embodiment, compound is a compound IV.In another embodiment, compound is compound V.In another embodiment, compound is a compound VI.In another embodiment, compound is compound VI I.In another embodiment, compound is a compound VIII.
SARM compound of the present invention and non-steroidal agonist compounds provide the remarkable superiority than steroid male sex hormone treatment, have the short male and anabolic activity of on-steroidal part of the androgen receptor of tissue selectivity in vivo because proved SARM compound of the present invention and non-steroidal agonist compounds.And, SARM compound of the present invention and non-steroidal agonist compounds are without severe side effect, oxidative metabolism ability, inconvenient administering mode or expensive, and have oral administration biaavailability, with other steroid receptor no cross reaction, and the advantage of growth transformation period.In one embodiment, compound is a Compound I.In another embodiment, compound is Compound I I.In another embodiment, compound is a compound III.In another embodiment, compound is a compound IV.In another embodiment, compound is compound V.In another embodiment, compound is a compound VI.In another embodiment, compound is compound VI I.In another embodiment, compound is a compound VIII.
Description of drawings
By following detailed description and in conjunction with the accompanying drawings, will understand more all sidedly and estimate the present invention, wherein:
Fig. 1: (S)-the short male and anabolic activity of GTx-007 in rat.Rat untreated (complete contrast), through castrating (castrating contrast), with testosterone propionate (TP) treatment or with the S-GTx-007 treatment, measure the weight of weight increase and male sex hormone sensitive organization (prostate gland, seminal vesicle and musculus levator ani).
The short male and anabolic activity of Fig. 2: S-GTx-007 in rat.Rat untreated (complete contrast), through castrating (castrating contrast), with 0.1,0.3,0.5,0.75 and 1.0mg/ day testosterone propionate (TP) treatment or with 0.1,0.3,0.5,0.75 and 1.0mg/ day S-GTx-007 treat the weight of mensuration male sex hormone sensitive organization (prostate gland, seminal vesicle and musculus levator ani).
The short male and anabolic activity of Fig. 3: S-GTx-014 in rat.Rat untreated (complete contrast), through castrating (castrating contrast), with 0.1,0.3,0.5,0.75 and 1.0mg/ day testosterone propionate (TP) treatment or with 0.1,0.3,0.5,0.75 and 1.0mg/ day S-GTx-014 treat the weight of mensuration male sex hormone sensitive organization (prostate gland, seminal vesicle and musculus levator ani).
Fig. 4: intravenous injection gives the mean plasma concentration-time curve behind beagle 3 and the 10mg/kg S-GTx-007.
Fig. 5: with the mean plasma concentration-time curve behind the solution form orally give beagle 10mg/kg S-GTx-007.
Fig. 6: give mean plasma concentration-time curve behind the beagle mg/kg S-GTx-007 with the capsule form intravenous injection.
Fig. 7: GTx-014 and GTx-007 are to the influence of LH level.
Fig. 8: GTx-014 and GTx-007 are to the influence of FSH level.
The synthetic route of Fig. 9: GTX-007.
Specific embodiments
The invention provides new class androgen receptor target agent (ARTA).This target agent defines the new subclass compound that those are tissue selective androgen receptor conditioning agents (SARM), they for oral testosterone replacement therapy, male contraception, keep women's sexual desire, treatment prostate cancer and prostate cancer imaging is useful.These reagent have the activity in vivo of short male and anabolic activity of the on-steroidal part of unexpected androgen receptor.These reagent may have activity separately, perhaps have activity with the associating of progesterone or oestrogenic hormon.The present invention further provides novel class of non-steroidal agonist compounds.The present invention further provides the composition that comprises selective androgen conditioning agent compound or non-steroidal agonist compounds, and in conjunction with androgen receptor, regulate spermatogeny, prostate cancer therapy and imaging method, and provide the hormonotherapy of the androgen-dependent patient's condition.
Compound definition as herein described shows potent anabolic action (for example muscle growth) and the new class SARM (SARMS) of less short male activity (for example prostate gland growth).This new class medicine has some non-selective androgenic advantages that exceed, be included in the potential treatment of regulating fertility, erythropoiesis, osteoporosis, sexual desire in the masculinity and femininity and use, and the potential treatment in suffering from the high-risk male sex of prostate cancer or prostate cancer is used.In one embodiment, compound is a Compound I.In another embodiment, compound is Compound I I.In another embodiment, compound is a compound III.In another embodiment, compound is a compound IV.In another embodiment, compound is compound V.In another embodiment, compound is a compound VI.In another embodiment, compound is compound VI I.In another embodiment, compound is a compound VIII.
In addition, in one embodiment, compound has the tissue specificity pharmacologically active.Shown in Fig. 7 and 8, GTx-007 does not suppress the LH level under the dosage of the maximal stimulation that can cause the musculus levator ani growth, and does not suppress the FSH level under the dosage of the maximal stimulation that can cause the musculus levator ani growth.
The present invention relates to the SARM compound, it has the short male and anabolic activity of the on-steroidal part of androgen receptor in the body of tissue selectivity, and this SARM compound is represented by formula I structure:
Figure A20051006749500221
Wherein X is O, CH 2, NH, Se, PR or NR;
Z is NO 2, CN, COR, COOH or CONHR;
Y is I, CF 3, Br, Cl or SnR 3
Q is alkyl, halogen, NR 2, NHCOCH 3, NHCOCF 3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3, NHCSCF 3, NHCSR, NHSO 2CH 3, NHSO 2R, OR, COR, OCOR, OSO 2R, SO 2R or SR, wherein R is aryl, C 1-C 4Alkyl, C 1-C 4Alkylhalide group, phenyl, halogen, alkenyl or hydroxyl; Perhaps Q be the condensed ring system that represents by structure A, B or C with the phenyl ring that it was connected:
Figure A20051006749500222
R is CH 3, CF 3, CH 2CH 3Or CF 2CF 3And
T be OH, OR ,-NHCOCH 3Or NHCOR, wherein R is C 1-C 4Alkyl, C 1-C 4Alkylhalide group, phenyl, halogen, alkenyl or hydroxyl.
In one embodiment, Q is in the contraposition of the phenyl ring that it connected.In another embodiment, Q is O in contraposition and X.In another embodiment, Q is in contraposition and be alkyl, halogen, NR 2, NHCOCH 3, NHCOCF 3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3, NHCSCF 3, NHCSR, NHSO 2CH 3, NHSO 2R, OR, COR, OCOR, OSO 2R, SO 2R or SR, wherein R is alkyl, aryl, C 1-C 4Alkyl, C 1-C 4Alkylhalide group, phenyl, halogen, alkenyl or hydroxyl.
The present invention relates to the SARM compound, it has the interior short male and anabolic activity of body of the on-steroidal part of androgen receptor, and this SARM compound is represented by formula II structure:
Figure A20051006749500231
Wherein X is O, CH 2, NH, Se, PR or NR;
Z is hydrogen bond receptor, NO 2, CN, COR, CONHR;
Y is fat-soluble group, I, CF 3, Br, Cl, SnR 3
R is alkyl or aryl or OH; And
Q is kharophen, trifluoroacetamido, alkylamine, ether, alkyl, N-alkylsulfonyl, O-alkylsulfonyl, alkyl sulphonyl, carbonyl or ketone.
The invention still further relates to the SARM compound, it has the interior short male and anabolic activity of body of the on-steroidal part of androgen receptor, and this SARM compound is represented by the formula III structure:
Wherein X is O, CH 2, NH, Se, PR or NR;
Z is NO 2, CN, COR or CONHR;
Y is I, CF 3, Br, Cl or SnR 3
R is alkyl or aryl or OH; And
Q is kharophen or trifluoroacetamido.
The invention still further relates to the SARM compound, it has short male and anabolic activity in the body of on-steroidal part of androgen receptor of tissue selectivity, and this SARM compound is represented by formula IV structure:
Figure A20051006749500241
The invention still further relates to the SARM compound, it has short male and anabolic activity in the body of on-steroidal part of androgen receptor of tissue selectivity, and this SARM compound is represented by formula V structure:
The invention still further relates to the SARM compound, it has short male and anabolic activity in the body of on-steroidal part of androgen receptor of tissue selectivity, and this SARM compound is represented by formula VI structure:
Figure A20051006749500243
The invention still further relates to the SARM compound, it has short male and anabolic activity in the body of on-steroidal part of androgen receptor of tissue selectivity, and this SARM compound is represented by formula VII structure:
The present invention relates to have the non-steroidal agonist compounds (compound VIII) of following formula structure:
Figure A20051006749500252
Wherein X is O, CH 2, NH, Se, PR or NR;
R 1Be CH 3, CF 3, CH 2CH 3Or CF 2CF 3
T be OH, OR ,-NHCOCH 3Or NHCOR, wherein R is C 1-C 4Alkyl, C 1-C 4Alkylhalide group, phenyl, halogen, alkenyl or hydroxyl;
A is 5 or 6 yuan of saturated, unsaturated or aromatic carbocyclic or heterocycles by following structure representative:
Figure A20051006749500253
Or
B is 5 yuan or 6 yuan of saturated, unsaturated or aromatic carbocyclic or heterocycles by following structure representative:
Or
Figure A20051006749500256
A wherein 1-A 11Each is C, O, S or N naturally;
B 1-B 11Each is C, O, S or N naturally;
Z is NO 2, CN, COR, COOH or CONHR;
Y is I, CF 3, Br, Cl or SnR 3And
Q 1And Q 2Be alkyl, halogen, NR independently of one another 2, NHCOCH 3, NHCOCF 3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3, NHCSCF 3, NHCSR, NHSO 2CH 3, NHSO 2R, OR, COR, OCOR, OSO 2R, SO 2R or SR, wherein R is C 1-C 4Alkyl, C 1-C 4Alkylhalide group, phenyl, halogen, alkenyl or hydroxyl.
Substituting group Z and Y can be in any positions of carrying these substituent 5 or 6 yuan of rings (hereinafter being called " A ring ").Similarly, substituting group Q can be in any position of carrying these substituent 5 or 6 yuan of rings (hereinafter being called " B ring ").Should be understood that as ring members A 1-A 11Or B 1-B 11In any ring members when being O or S, these ring memberses are unsubstituted so.Should also be understood that as ring members A 1-A 11Or B 1-B 11In any ring members when being O or S, the dotted line between described ring members and other ring members is represented singly-bound so.
In one embodiment, the A ring comprises the saturated or unsaturated carbocyclic of any kind.In one embodiment, A ring is 6 yuan of saturated carbon rings, its can be unsubstituted, replaced by above-described any substituting group list or polysubstituted.In one embodiment, A ring is 5 yuan of saturated carbon rings, its can be unsubstituted, replaced by above-described any substituting group list or polysubstituted.In another embodiment, A ring is 6 yuan of carbocyclic rings that contain one or more pairs of keys, its can be unsubstituted, replaced by above-described any substituting group list or polysubstituted.In another embodiment, A ring is 5 yuan of carbocyclic rings that contain one or more pairs of keys, its can be unsubstituted, replaced by above-described any substituting group list or polysubstituted.
In another embodiment, the A ring comprises saturated, the unsaturated or aromatic heterocycle of any kind.In another embodiment, A ring is 6 yuan of saturated heterocyclics, its can be unsubstituted, replaced by above-described any substituting group list or polysubstituted.In another embodiment, A ring is 5 yuan of saturated heterocyclics, its can be unsubstituted, replaced by above-described any substituting group list or polysubstituted.In another embodiment, A ring is 6 yuan of heterocycles that contain one or more pairs of keys, its can be unsubstituted, replaced by above-described any substituting group list or polysubstituted.In another embodiment, A ring is 5 yuan of heterocycles that contain one or more pairs of keys, its can be unsubstituted, replaced by above-described any substituting group list or polysubstituted.In another embodiment, A ring is 6 yuan of heterocycles, its can be unsubstituted, replaced by above-described any substituting group list or polysubstituted.In another embodiment, A ring is 5 yuan of heterocycles, its can be unsubstituted, replaced by above-described any substituting group list or polysubstituted.
Similarly, the B ring comprises the saturated or unsaturated carbocyclic of any kind.In one embodiment, B ring is 6 yuan of saturated carbon rings, its can be unsubstituted, replaced by above-described any substituting group list or polysubstituted.In one embodiment, B ring is 5 yuan of saturated carbon rings, its can be unsubstituted, replaced by above-described any substituting group list or polysubstituted.In another embodiment, B ring is 6 yuan of carbocyclic rings that contain one or more pairs of keys, its can be unsubstituted, replaced by above-described any substituting group list or polysubstituted.In another embodiment, B ring is 5 yuan of carbocyclic rings that contain one or more pairs of keys, its can be unsubstituted, replaced by above-described any substituting group list or polysubstituted.
In another embodiment, the B ring comprises saturated, the unsaturated or aromatic heterocycle of any kind.In another embodiment, B ring is 6 yuan of saturated heterocyclics, its can be unsubstituted, replaced by above-described any substituting group list or polysubstituted.In another embodiment, B ring is 5 yuan of saturated heterocyclics, its can be unsubstituted, replaced by above-described any substituting group list or polysubstituted.In another embodiment, B ring is 6 yuan of heterocycles that contain one or more pairs of keys, its can be unsubstituted, replaced by above-described any substituting group list or polysubstituted.In another embodiment, B ring is 5 yuan of heterocycles that contain one or more pairs of keys, its can be unsubstituted, replaced by above-described any substituting group list or polysubstituted.In another embodiment, B ring is 6 yuan of heterocycles, its can be unsubstituted, replaced by above-described any substituting group list or polysubstituted.In another embodiment, B ring is 5 yuan of heterocycles, its can be unsubstituted, replaced by above-described any substituting group list or polysubstituted.
The suitable A ring and/or the limiting examples of B ring are carbocyclic ring such as pentamethylene, cyclopentenes, hexanaphthene and cyclohexene ring, and heterocycle such as pyrans, dihydropyrane, tetrahydropyrans, pyrroles, pyrrolin, Pyrrolidine, pyrazine, dihydro pyrazine, tetrahydrochysene pyrazine, pyrimidine, dihydro-pyrimidin, tetrahydropyrimidine, pyrazoles, pyrazoline, tetrahydro-pyrazole, piperidines, piperazine, pyridine, dihydropyridine, tetrahydropyridine, morpholine, thiomorpholine, furans, dihydrofuran, tetrahydrofuran (THF), thiophene, dihydro-thiophene, tetramethylene sulfide, thiazole, imidazoles, isoxazole etc.
As used herein, the acceptor of extracellular signaling molecule is referred to as " cell signal acceptor " (cellsignaling receptor).Many cell signal acceptors are transmembrane proteins of cell surface; When they during in conjunction with extracellular signaling molecule (being part), thereby they become the activation form and cause the intracellular signal cascade that changes cell behavior.On the contrary, sometimes acceptor is in cell, and the signal part must enter cell and activate them; Thereby these signaling molecules must be enough little and hydrophobic, to cross over the cytoplasmic membrane diffusion.As used herein, these acceptors are referred to as " born of the same parents' inner cell frizzled receptor ".
Steroid hormone be directly cross over target cell plasma membrane diffusion or transhipment and with an example of the little hydrophobic molecule of born of the same parents' inner cell frizzled receptor bonded.The structurally relevant and formation intracellular receptor superfamily (or steroid hormone receptor superfamily) of these acceptors.Steroid hormone receptor comprises PgR, estrogen receptor, androgen receptor, glucocorticoid receptor and mineralcorticoid receptor, and many orphan receptors.The present invention is especially at androgen receptor and all isotypes thereof.
Except that part is incorporated into acceptor, can block acceptor to prevent the part combination.When material and receptors bind, the three-dimensional structure of this material is fit to the space of the three-dimensional structure formation of this receptor with ball-and-socket form (ball and socketconfiguration).
The suitable more nest of ball, then it is closely kept more.This phenomenon is called affinity.If the affinity of material is enough high, it will and combine binding site more frequently with the hormone competition so.The combination of part also can cause other important proteic tissue selectivity to be raised with transduction signal.These albumen are called as association's activator (coactivator) and association's co-inhibitor, participate in signal transduction, and can be by part in conjunction with optionally inducing or suppressing.In case combination, signal just can be sent in the cell by acceptor, cause that cell replys in some way.This is called activation.After the activation, the activated acceptor is directly regulated transcribing of specific gene.But material and acceptor may have some attribute of the activating cells outside the affinity.Between the atom of the atom of material and acceptor, can form chemical bond.Sometimes, this causes the change of acceptor configuration, thereby is enough to start activation process (being called signal transduction).As a result, produce bind receptor and activate their material (being called receptor stimulant) or make the material (being called the receptor antagonist body) of their inactivations.
The present invention is directed to the SARM compound, they are agonist compounds, thus in conjunction with and activate aspect the steroid hormone receptor useful.These compounds are non-steroids.Preferably, agonist compound of the present invention is the agonist in conjunction with androgen receptor.Preferably, this compound has high affinity for androgen receptor.Compound both can reversibly also can irreversibly combine with androgen receptor.Compound of the present invention can contain the functional group's (affinity labelling) that allows androgen receptor alkylation (being that covalent linkage forms).Therefore, in this case, compound irreversibly combines with acceptor, and thereby can not be replaced by steroid such as endogenous ligands dihydrotestosterone and testosterone.Yet preferred compound of the present invention reversibly combines with androgen receptor.
According to an aspect of the present invention, provide by effectively causing under SARM compound of the present invention and the androgen receptor bonded condition, this receptor is contacted with the SARM compound and make SARM compound and androgen receptor bonded method.The SARM compound makes compound of the present invention be applicable to the multiple hormonotherapy of masculinity and femininity with combining of androgen receptor.The agonist compound combination also activates androgen receptor.The combination of agonist compound or reversible or irreversible, preferably reversible.
According to an aspect of the present invention, provide, by SARM compound and androgen receptor effectively being combined and increasing or reducing under the condition of sperm generation, patient's androgen receptor is contacted with the SARM compound, and regulate spermatogenetic method.
According to another aspect of the present invention, the patient is provided the hormonotherapy of (promptly suffering from the androgen-dependent patient's condition), be included in and make SARM compound and androgen receptor effectively combine and realize under the condition of change of the androgen-dependent patient's condition patient's androgen receptor to be contacted with the SARM compound.According to the present invention, the androgen-dependent patient's condition that can be treated comprises those and the aging relevant patient's condition, determines to depend on the patient's condition of low male sex hormone (for example testosterone) level afterwards as hypogonadism, Sarcopenia, erythropoiesis, osteoporosis and any other.In one embodiment, the SARM compound is individually dosed.In another embodiment, SARM compound and progesterone Combined Preparation.In another embodiment, SARM compound and oestrogenic hormon Combined Preparation.
According to a further aspect in the invention, provide treatment to suffer from the experimenter's of prostate cancer method.Described method comprises the SARM compound that gives experimenter's significant quantity.In one embodiment, the SARM compound is optionally to male sex hormone or testosterone receptor.
The invention still further relates to treatment and suffer from the experimenter's of chronic amyotrophy morbid state method, be included in and make SARM compound and androgen receptor effectively combine and realize under the condition of change of the androgen-dependent patient's condition described experimenter's androgen receptor to be contacted with the SARM compound.In one embodiment, the SARM compound is optionally to male sex hormone or testosterone receptor.The invention still further relates to the method for orally give SARM compound.In one embodiment, compound is a Compound I.In another embodiment, compound is Compound I I.In another embodiment, compound is a compound III.In another embodiment, compound is a compound IV.In another embodiment, compound is compound V.In another embodiment, compound is a compound VI.In another embodiment, compound is compound VI I.In another embodiment, compound is a compound VIII.
According to an aspect of the present invention, provide by effectively causing under non-steroidal agonist compounds of the present invention and the androgen receptor bonded condition, this receptor is contacted with non-steroidal agonist compounds, and make non-steroidal agonist compounds and androgen receptor bonded method.Non-steroidal agonist compounds makes compound of the present invention be applicable to the multiple hormonotherapy of masculinity and femininity with combining of androgen receptor.The agonist compound combination also activates androgen receptor.The combination of agonist compound or reversible, or irreversible, preferably reversible.
According to an aspect of the present invention, provide by SARM compound and androgen receptor effectively being combined and increasing or reduce under the condition of sperm generation, patient's androgen receptor is contacted with the SARM compound, and regulate spermatogenetic method.
According to another aspect of the present invention, the patient is provided the hormonotherapy of (individuality of promptly suffering from the androgen-dependent patient's condition), be included in and make non-steroidal agonist compounds and androgen receptor effectively combine and realize under the condition of change of the androgen-dependent patient's condition patient's androgen receptor to be contacted with non-steroidal agonist compounds.According to the present invention, the androgen-dependent patient's condition that can be treated comprises those ageing-related the patient's condition, as hypogonadism, Sarcopenia, erythropoiesis, osteoporosis, shortage sexual desire and any patient's condition of determining to depend on low male sex hormone (for example testosterone) level afterwards.In one embodiment, non-steroidal agonist compounds is individually dosed.In another embodiment, non-steroidal agonist compounds and progesterone Combined Preparation.In another embodiment, non-steroidal agonist compounds and oestrogenic hormon Combined Preparation.
According to a further aspect in the invention, provide treatment to suffer from the experimenter's of prostate cancer method.Described method comprises the non-steroidal agonist compounds that gives experimenter's significant quantity.In one embodiment, non-steroidal agonist compounds is optionally to male sex hormone or testosterone receptor.
Compound of the present invention has asymmetric center, and can be R or S isomer, the perhaps mixture of the two.In one embodiment, compound is the racemic mixture of R and S enantiomorph.In another embodiment, compound is pure basically R enantiomorph.In another embodiment, compound is pure basically S enantiomorph." pure basically " is defined as a kind of isomer comprises in this article greater than about 95% advantage.When the above-mentioned method for preparing compound used therefor of the present invention obtains stereoisomer mixture, can pass through routine techniques, as preparative chromatography, separate these isomer.Compound can be prepared into the racemization form, and is perhaps synthetic or prepare one enantiomorph by fractionation by the mapping specificity.
As used herein, " pharmaceutical composition " refers to treat the SARM of the present invention or the non-steroidal agonist compounds of significant quantity and is in the same place with suitable thinner, sanitas, solubilizing agent, emulsifying agent, assistant agent and/or carrier.As used herein, " treatment significant quantity " refers to provide the amount of curative effect for the given patient's condition and dosage regimen.This composition is liquid or freeze dried or other exsiccant prescriptions, and comprise various buffer compositions (Tris-HCl for example, acetate, phosphoric acid salt), the thinner of pH and ionic strength, prevent to be adsorbed in additive such as the albumin or the gelatin on surface, stain remover (polysorbas20 for example, tween 80, Pluronic F68, bile salt), solubilizing agent (glycerine for example, polyoxyethylene glycol), antioxidant (xitix for example, Sodium Pyrosulfite), sanitas (thimerosal for example, phenylcarbinol, p-Hydroxybenzoate), increment (bulking) material or tension force properties-correcting agent (lactose for example, N.F,USP MANNITOL), covalently bound polymkeric substance is as being connected in proteic polyoxyethylene glycol, cooperate with metal ion, or material mixed polymkeric substance such as poly(lactic acid), polyglycolic acid, in the particle product of hydrogel etc. or on it, perhaps mix liposome, micro emulsion, micella, the single or multiple lift vesica, on blood shadow or the spheroplast.This composition will influence rate of release and the interior clearance rate of body in physical condition, solubleness, stability, the body.Controlled release or slow releasing composition are included in the prescription in the lipotropy storage storehouse (for example lipid acid, wax, oil).
The present invention also comprises with polymkeric substance (for example poloxamer or poloxamines) coated granules composition.Other embodiment of composition of the present invention comprises and is used for various route of administration, comprise intestines outer, through lung, intranasal and oral particle form, protectiveness dressing, proteinase inhibitor or penetration enhancers.In one embodiment, pharmaceutical composition is through following administration: (paracancerally) outside the intestines, outside the cancer knurl, through mucous membrane, in skin, intramuscular, intravenously, intracutaneous, subcutaneous, intraperitoneal, ventricle, in encephalic and the tumour.
In addition, as used herein, " pharmaceutically acceptable carrier " is well known to those skilled in the art, and includes but not limited to 0.01-0.1M and preferred 0.05M phosphate buffered saline buffer or 0.8% salt solution.In addition, this type of pharmaceutically acceptable carrier can be moisture or non-aqueous solution, suspension and emulsion.Examples of non-aqueous is propylene glycol, polyoxyethylene glycol, vegetables oil such as sweet oil, and injectable organic ester such as ethyl oleate.Aqueous carrier comprises water, ethanol/water solution, emulsion or suspension, comprises salt solution and buffering medium.
The outer carrier of intestines comprises sodium chloride solution, Ringer ' s dextrose, dextrose and sodium-chlor, lactic acid Ringer ' s or fixed oil.Intravenous vehicles comprises liquid and nutritional supplement, dielectric medium fill-in as based on those of Ringer ' s dextrose, or the like.Also can contain sanitas and other additive, for example biocide, antioxidant, finishing composition (collatingagents), rare gas element etc.
Controlled release or slow releasing composition are included in the prescription in the lipotropy storage storehouse (for example lipid acid, wax, oil).The present invention also comprises with polymkeric substance (for example poloxamer or poloxamines) coated granules composition, and compound is coupled on antibody, part or the antigen at the tissue specificity acceptor, perhaps is coupled on the part of tissue specificity acceptor.
Other embodiment of composition of the present invention comprises and is used for various route of administration, comprise intestines outer, through lung, intranasal and oral particle formulation, protectiveness dressing, proteinase inhibitor or penetration enhancers.
The compound of the covalently bound modification of known multipolymer, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone or polyproline by water-soluble polymers such as polyoxyethylene glycol, polyoxyethylene glycol and polypropylene glycol is after intravenous injection, in blood, demonstrate than remarkable longer transformation period (Abuchowski etc., 1981 of the compound of corresponding unmodified; Newmark etc., 1982; With Katre etc., 1987).These modifications also may increase solubleness, the elimination of compound in the aqueous solution assembles, improves the physics and the chemical stability of compound, and greatly reduces the immunogenicity and the reactivity of compound.As a result, by giving this polymkeric substance-compound adducts (abducts), can realize the biological activity of expecting to compare lower frequency and lower dosage with the compound of unmodified.
In another embodiment, pharmaceutical composition can be through the controlled release system administration.For example, can use venoclysis, implantable osmotic pump, transdermal patch, liposome or other administering mode to give medicine.In one embodiment, can use pump (, above-mentioned referring to Langer; Sefton, CRC Crit.Ref.Biomed.Eng.14:201 (1987); Buchwald etc., Surgery 88:507 (1980); Saudek etc., N.Engl.J.Med.321:574 (1989).In another embodiment, can use polymeric material.In another embodiment, controlled release system can be positioned over the treatment target, promptly brain near, thereby only need body dose a part (referring to for example, Goodson, in Medical Applications of ControlledRelease, above-mentioned, vol.2, pp.115-138 (1984).Preferably, near controlled-release device introducing unfavorable immuno-stimulating of experimenter or the tumour.Other controlled release system (Science 249:1527-1533 (1990) has been discussed in the summary of Langer.
Pharmaceutical preparation can only comprise SARM, perhaps also comprise pharmaceutically acceptable carrier, and can be solid or liquid form, as tablet, powder, capsule, piller, solution, suspensoid, elixir, emulsion, gelifying agent, emulsifiable paste or suppository, comprise rectum and urethral suppositories.Pharmaceutically acceptable carrier comprises gel, starch, sugar, cellulosic material and their mixture.The pharmaceutical preparation that contains SARM can be given and the experimenter by for example subcutaneous implantation piller; In another embodiment, piller provides the sustained release of SARM in one period.Preparation also can pass through intravenously, intra-arterial or intramuscularly liquid preparation, orally give liquid or solid preparation, or gives by topical application.Also can finish administration by using rectal suppository or urethral suppositories.
Pharmaceutical preparation of the present invention can prepare by known dissolving, mixing, granulation or tabletting method.For oral administration, derivative that can tolerate SARM or its physiology such as salt, ester, N-oxide compound etc. mix with additive such as carrier, stablizer or inert diluent that routine is used for this purpose, and be converted into the suitable form that is used for administration by ordinary method, as tablet, coated tablet, hard or soft gelatin capsule, water, alcohol or oil solution.The example of suitable inert support is conventional tablet matrix such as lactose, sucrose or W-Gum and tackiness agent such as Sudan Gum-arabic, W-Gum, gelatin, perhaps with disintegrating agent such as W-Gum, yam starch, alginic acid, perhaps with lubricant such as stearic acid or Magnesium Stearate.
The suitable oily carrier or the example of solvent are vegetables oil or animal oil, as sunflower oil or Oils,glyceridic,cod-liver.Preparation can be used as dried particle or wet granular obtains.For intestines external administration (subcutaneous, intravenously, intra-arterial or intramuscularly), the derivative of SARM agent or on-steroidal agonist or the tolerance of their physiology such as salt, ester, N-oxide compound etc. are changed into solution, suspension or emulsion, if expectation is with habitual and be suitable for this desired substance for example solubilizing agent or other assistant agent are prepared.Example is: sterile liquid Ru Shui and oil, add or do not add tensio-active agent and the acceptable assistant agent of other pharmacy.The example of oil is to derive from oil, animal, plant or synthetic oil, for example peanut oil, soybean oil or mineral oil.Usually, water, salt solution, the dextrose aqueous solution and relevant sugar soln, and glycol such as propylene glycol or polyoxyethylene glycol be preferred liquid vehicle, particularly uses for injection solution.
The preparation of drug combination that contains active ingredient is well known in the art.Usually, these preparation of compositions are become to be administered into the polypeptide aerosol of pharynx nasalis, perhaps be prepared into injecting fluid solution or suspension, yet, also can be prepared into the solid form that is dissolved in or is suspended in before being adapted at injecting in the liquid.Preparation also can be emulsified.The active treatment composition is acceptable and compatible with the activeconstituents mixed with excipients with pharmacy usually.Suitable vehicle is for example water, salt solution, dextrose, glycerine, ethanol etc. and their combination.
In addition, if expectation, composition can contain minor amounts of auxiliary substances, and as wetting agent or emulsifying agent, pH buffer reagent, these auxiliary substances improve the validity of activeconstituentss.
Active ingredient can be filled a prescription in composition with neutral pharmacologically acceptable salts form.Pharmacologically acceptable salts comprises acid salt (forming with the free amino group of polypeptide or antibody molecule), and they are the salt that forms with mineral acid example hydrochloric acid or phosphoric acid, or the salt that forms with organic acid such as acetic acid, oxalic acid, tartrate, mandelic acid, or the like.The salt that is formed by free carboxyl group also can derive from mineral alkali such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide or ironic hydroxide etc., derives from organic bases such as Isopropylamine, Trimethylamine 99,2-ethylamino-ethanol, Histidine, PROCAINE HCL, PHARMA GRADE etc.
For to the body surface topical, for example use emulsifiable paste, gelifying agent, drops etc., the derivative of preparation SARM agent or non-steroidal agonist compounds or the tolerance of their physiology such as salt, ester, N-oxide compound etc., and with in the physiology acceptable diluent, the solution, suspension or the emulsion form that are with or without pharmaceutical carrier are used.
In another embodiment, active compound can be with vesica, and especially liposome administration (referring to Langer, Science 249:1527-1533 (1990); Treat etc., in Liposomesin the Therapy of infectious Disease and Cancer, Lopez-Berestein andFidler (eds.), Liss, New York, pp.353-365 (1989); Lopez-Berestein, ibid, pp.317-327; Generally referring to, ibid).
For medical use, the salt of SARM or non-steroidal agonist compounds is pharmacologically acceptable salts.Yet other salt comes in handy in preparation compound of the present invention or their pharmacologically acceptable salts.The suitable pharmacologically acceptable salts of compound of the present invention comprises acid salt, it can, for example mix with the solution of the acceptable acid of pharmacy and make the acceptable sour example hydrochloric acid of described pharmacy, sulfuric acid, methylsulfonic acid, fumaric acid, toxilic acid, succsinic acid, acetic acid, phenylformic acid, oxalic acid, citric acid, tartrate, carbonic acid or phosphoric acid by the solution that makes compound of the present invention.
The invention further relates to the method for the existence of determining selective androgen conditioning agent compound of the present invention in the sample and/or non-steroidal agonist compounds.Described method comprises the following steps: to obtain sample, detects the compound in the sample, thereby determines the existence of compound in sample.
In one embodiment, sample is a serum sample.In another embodiment, sample is a plasma sample.In another embodiment, sample is a urine sample.In another embodiment, sample is a saliva sample.In another embodiment, sample is any other tissue samples.
In one embodiment, detect step and be included in the absorbancy that predetermined wavelength is measured compound.For example, compound of the present invention absorbs in the spectrographic ultraviolet region, and absorption peak is at 270nm.Therefore, in one embodiment of the invention, come detection compound in the UV of 270nm absorbancy by monitor sample.Should be noted that the invention is not restricted to UV absorbs, any other spectroscopic identification method all is suitable for.For example, detect them by measuring the absorbancy of compound in infrared region or visible region.
In another embodiment, the present invention further provides the method for measuring SARM compound of the present invention in the sample and/or non-steroidal agonist compounds concentration.Described method comprises the following steps: to obtain sample; Measure the level of compound in the sample, compare, calculate the concentration of compound in sample by level with the standard model that contains the concentration known compound.Can obtain the calibration curve of the concentration known of compound in the sample.Calculate compound concentrations the test sample book from calibration curve." level " refers to that compound is in the absorption level of measuring wavelength.
In another embodiment, detect the compound in the sample through the following steps: make sample and the compound bonded is conjugated protein contacts with this specifically, measure the protein-bonded amount that is incorporated into this compound.Be incorporated into the protein-bonded amount of this compound by mensuration, and will measure with the standard model that contains the compound-conjugated protein mixture of concentration known and compare, can record compound concentrations.
According to standard technique, can measure protein level as descriptions such as Sambrook.In brief, make from experimenter's sample with specifically with conjugated protein contact of specific compound bonded of the present invention, measure the amount of the mixture that forms between conjugated protein and the compound.In one embodiment, conjugated protein be specifically with one or more compound bonded antibody of the present invention.In another embodiment, conjugated protein have a detectable label that connects on it, and the mixture between-tagged compound conjugated protein by observing is measured this mixture.
As defined herein, " contact " refer in the sample in conjugated protein introducing test tube, flask, tissue culture, chip (chip), array (array), flat board, microplate, the kapillary etc., and carry out incubation being enough to make the part that contains target in conjunction with component and cell or its or plasma or its to contain under the part bonded temperature and time of target.Sample is conventionally known to one of skill in the art with method conjugated protein or that other specific binding component contacts, and can be selected according to the type of the experimental program of taking.The incubation method also is a standard, and is conventionally known to one of skill in the art.
Can finish " observation " mixture by any method known in the art, described method includes but not limited to immunohistochemistry, HPLC and the mass spectrum of ELISA, radioimmunoassay, flow cytometry, Dot blot, western immunoblotting associating gel electrophoresis, light and electronic horizon.
In various immunoassay, can use selective androgen conditioning agent compound of the present invention or specific mono-clonal of non-steroidal agonist compounds or polyclonal antibody (and any recombinant antibodies).Use conventional labeling technique well-known in the art, antibody can be able to be detected ground mark.As used herein, term " mark " refers to put together or to connect (promptly covalently or non-covalently) in protein-bonded molecule defined herein.Be labeled as conventionally known to one of skill in the art.Therefore, can use technology well known in the art, can come traget antibody with radio isotope, non radioactive isotope mark, fluorescent mark, enzyme labelling, chemiluminescent labeling, bioluminescence marker, free radical mark or phage mark.The example of labelled with radioisotope is 3H, 125I, 131I, 35S, 14C etc.The example of non radioactive isotope mark is 55Mn, 56Fe etc.Fluorescently-labeled example is the fluorescent mark with the direct mark of preferred fluorescent mark, or with the fluorescent mark of preferred fluorescent mark indirect labelling.Under latter event, preferred fluorescent mark is puted together in the second antibody at first antibody, as anti-kind of Ig antibody.Conventional fluorescent mark includes but not limited to, the luciferin mark, the lsothiocyanates mark, the rhodamine mark, phycoerythrin mark etc., Fluorescein Isothiocyanate (FITC for example, InternationalBiological Supplies, Melbourne, PL), rhodamine, phycoerythrin (P.E., CoulterCorp., Hialeah, FL), Phycocyanins, C-, allophycocyanin (alophycocyanin), phycoerythrin-anthocyanin dye 5 (PECy5, Coulter) mark, the Phycocyanins, C-mark, the allophycocyanin mark, o-phthalaldehyde(OPA) (O-phthaldehyde) mark, fluorescamine and texas Red (Texas Red).
The example of enzyme labelling comprises alkaline phosphatase, beta-galactosidase enzymes, glucose-6-phosphate dehydrogenase (G6PD), toxilic acid desaturase and peroxidase.The enzyme immunoassay of two kinds of main types is enzyme-linked immunosorbent assay (ELISA) and homology enzyme immunoassay, also be called enzyme amplify immunoassay (EMIT, Syva Corporation, Palo Alto, CA).In the ELISA system, the antibody that can be for example be coupled to solid phase by use separates.The EMIT system depends on the inactivation of enzyme in the tracer antibody mixture; Therefore, need not separating step and can measure activity.
Shi Yi mark comprises those that permission is analyzed by flow cytometry, for example fluorescence dye especially.Other suitable detectable label comprises the mark that is used for the colorimetric enzyme system, for example horseradish peroxidase (HRP) and alkaline phosphatase (AP).Other close enzyme system is conventionally known to one of skill in the art, comprises the hexokinase of puting together with glucose-6-phosphate dehydrogenase (G6PD).
In addition, chemiluminescence compound can be with marking.Chemiluminescent labeling is known as green fluorescent protein, blue fluorescent protein and their variant.Use respectively to have the NAD oxydo-reductase of luciferase and substrate NADH and FNIN and have luminol,3-aminophthalic acid cyclic hydrazide and the peroxidase of enzyme substrates superoxide, also can the luminous or chemoluminescence of detection of biological.The conventional chemical luminophor comprises luminol,3-aminophthalic acid cyclic hydrazide, different luminol,3-aminophthalic acid cyclic hydrazide (isoluminol), aromatics acridine (acridinium) ester, imidazoles, acridinium salt and barkite.Similarly, bioluminescent compound can be used for mark, and bioluminescent compound comprises luciferin, luciferase and aequorin.In case be labeled, utilize technology well-known in the art, can use antibody to discern and quantitative immune complement (antibody or antigenic peptide).
Following examples are used for more fully explaining the preferred embodiments of the invention.Yet they are anything but in order to limit wide protection domain of the present invention.
The experimental detail part
Embodiment 1
On-steroidal part with short male and anabolic activity
The SARM compound that design, synthetic this paper are provided, and estimate its external and interior pharmacological activity of body.Studied external androgen receptor in conjunction with affinity and the ability of keeping androgen-dependent tissue growth in the neuter.Keep and/or stimulate the ability of prostate gland and seminal vesicle growth to monitor short male activity by the SARM compound, prostate gland and seminal vesicle growth obtain by gravimetry.Keep and/or stimulate the ability of musculus levator ani growth to monitor anabolic activity by the SARM compound, the musculus levator ani growth obtains by gravimetry.
The building-up process of Compound I-VIII:
(2R)-1-methacryloyl tetramethyleneimine-2-carboxylic acid (R-129).(R-128,14.93g 0.13mol) are dissolved among the 71mL 2N NaOH, and cool off in ice bath with the D-proline(Pro); Basic solution with acetone (71mL) dilution gained.In 40min, (13.56g, acetone soln 0.13mol) (71mL) and 2N NaOH solution (71mL) add in the D-proline(Pro) aqueous solution in the ice bath simultaneously with methacrylic chloride 127.During adding methacrylic chloride, the pH of mixture is remained on 10-11 ℃.After stirring (3h, room temperature), under 35-45 ℃ temperature, the vacuum-evaporation mixture is to remove acetone.With the solution of ether washing gained, and be acidified to pH 2 with dense HCl.With the saturated acidic mixture of NaCl, and extract (100mL * 3) with EtOAc.With the extract Na that merges 2SO 4Drying is filtered through C salt, and vacuum-evaporation, obtains the colorless oil crude product.Recrystallization should oil from ether and hexane, obtains the clear crystal of 16.2 (68%) desired compounds: mp 102-103 ℃ (lit.[214] mp 102.5-103.5 ℃); The NMR stave of this compound is bright, has two kinds of rotational isomers of title compound. 1H NMR (300MHz, DMSO-d 6) δ is for first kind of rotational isomer 5.28 (s) and 5.15 (s), for second kind of isomer 5.15 (s) and 5.03 (s) (two kinds of all total 2H of isomer, vinyl CH 2), for first kind of isomer 4.48-4.44, for second kind of isomer 4.24-4.20 (m) (two kinds of all total 1H of isomer, the CH of chiral centre), 3.57-3.38 (m, 2H, CH 2), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH 2, CH, Me); 13C NMR (75MHz, DMSO-d 6) δ 173.3,169.1,140.9,116.4,58.3,48.7,28.9,24.7,19.5 of main rotational isomer; The δ 174.0,170.0,141.6,115.2,60.3,45.9,31.0,22.3,19.7 of less isomer; IR (KBr) 3437 (OH), 1737 (C=O), 1647 (CO, COOH), 1584,1508,1459,1369,1348,1178cm -1[α] D 20+ 80.8 ° (c=1, MeOH); C 9H 13NO 3The analytical calculation value: C 59.00, and H 7.15, and N 7.65. measured value: C 59.13, and H 7.19, and N 7.61.
(3R, 8aR)-3-brooethyl-3-methyl-tetrahydrochysene-pyrrolo-[2,1c] [1,4] oxazine-1, and the 4-diketone (R, R-130).Under the room temperature argon gas, will (23.5g, 0.132mol) drips of solution be added to compound R-129 (16.1g 88mmol) in the stirred solution of 70mL DMF, and stirs the mixture of gained 3 days at the NBS among the 100mL DMF.Solvent removed in vacuo is settled out yellow solid.Solid suspension in water, is stirred under the room temperature and spends the night, filter and dry, when dry (weight diminish～34%) the title compound yellow solid that obtains 18.6 (81%): mp 152-154 ℃ (lit.[214] S-isomer mp 107-109 ℃); 1H NMR (300MHz, DMSO-d 6) δ 4.69 (dd, J=9.6Hz, J=6.7Hz, 1H, chiral centre CH), 4.02 (d, J=11.4Hz, 1H, CHH a), 3.86 (d, J=11.4Hz, 1H, CHH b), 3.53-3.24 (m, 4H, CH 2), 2.30-2.20 (m, 1H, CH), 2.04-1.72 (m, 3H, CH 2And CH), 1.56 (s, 2H, Me); 13C NMR (75MHz, DMSO-d 6) δ 167.3,163.1,83.9,57.2,45.4,37.8,29.0,22.9,21.6; IR (KBr) 3474,1745 (C=O), 1687 (C=O), 1448,1377,1360,1308,1227,1159,1062cm -1[α] D 26+ 124.5 ° (c=1.3, chloroform); C 9H 12BrNO 3The analytical calculation value: C 41.24, and H 4.61, and N 5.34. measured value: C 41.46, and H 4.64, and N 5.32.
(2R)-3-bromo-2-hydroxy-2-methyl propionic acid (R-131).Will be at bromine lactone R-130 (18.5g, 71mmol) the mixture heating up backflow 1h among the 300mL 24%HBr.With the solution of salt solution (200mL) dilution gained, and with ethyl acetate extraction (100mL * 4).Use saturated NaHCO 3The extract (100mL * 4) that washing merges.With dense HCl acidified aqueous solution to pH=1, and then with ethyl acetate extraction (100mL * 4) it.With the organic solution Na that merges 2SO 4Drying is filtered through C salt, and vacuum-evaporation is to doing.Recrystallization obtains the clear crystal of 10.2g (86%) desired compounds from toluene: mp 107-109 ℃ (lit.[214] S-isomer 109-113 ℃); 1H NMR (300MHz, DMSO-d 6) δ 3.63 (d, J=10.1Hz, 1H, CHH a), 3.52 (d, J=10.1Hz, 1H, CHH b), 1.35 (s, 3H, Me); IR (KBr) 3434 (OH), 3300-2500 (COOH), 1730 (C=O), 1449,1421,1380,1292,1193,1085cm -1[α] D 26+ 10.5 ° (c=2.6, MeOH); C 4H 7BrO 3The analytical calculation value: C 26.25, and H 3.86. measured value: C 26.28, and H 3.75.
N-[4-nitro-3-(trifluoromethyl) phenyl]-(2R)-3-bromo-2-hydroxy-2-methyl propionic acid amide (R-132).Under argon gas and-5 to-10 ℃, (8.6g, (11.0g is 60mmol) in the solution 72mmol) to be added drop-wise to bromo-acid R-131 in 70mL DMA with thionyl chloride.Mixture with gained stirs 2h under the same conditions.In above solution, drip 4-nitro-3-trifluoromethyl-aniline in 80mL DMA (12.4g, 60mmol) solution, and the mixture of gained at room temperature stirred spend the night.Using the high vacuum oil pump to remove in Rotavapor desolvates; With saturated NaHCO 3The solution dilution resistates, and with ether extraction (100mL * 3).The extract that merges is through anhydrous Na 2SO 4Drying is filtered through C salt, and uses methylene dichloride to pass through the flash chromatography purifying as eluent on silica gel, obtains 18.0g (80%) desired compounds: mp 98-100 ℃ (R f=0.2, silica gel, CH 2Cl 2); 1H NMR (300MHz, DMSO-d 6) δ 10.54 (s, 1H, NH), 8.54 (d, J=2.1Hz, 1H, ArH), 8.34 (dd, J=9.0Hz, J=2.1Hz, 1H, ArH), 8.18 (d, J=9.0Hz, 1H, ArH), 6.37 (s, 1H, OH), 3.82 (d, J=10.4Hz, 1H, CHH a), 3.58 (d, J=10.4Hz, 1H, CHH b), 1.48 (s, 3H, Me); 13C NMR (75MHz, DMSO-d 6) δ 173.6 (C=O), 143.0,127.2,123.2,122.6 (q, J=33.0Hz), 122.0 (q, J=271.5Hz), 118.3 (q, J=6.0Hz), 74.4,41.4,24.9; IR (KBr) 3344 (OH), 1680 (C=O), 1599,1548 (C=C, Ar), 1427,1363,1161cm -1MS (ESI): m/z 370.8 (M) +C 11H 10BrN 2O 4The analytical calculation value: C 35.60, and H 2.72, and N 7.55. measured value: C 35.68, and H 2.72, and N 7.49.
N-[4-nitro-3-(trifluoromethyl) phenyl]-(2S)-3-[4-(kharophen) phenoxy group]-2-hydroxy-2-methyl propionic acid amide (S-147).By compound R-132 (0.37g, 1.0mmol), the 4-acetoamidophenol (0.23g, 1.5mmol), K 2CO 3(10% zephiran chloride, the three fourth ammoniums in the 20mL methyl ethyl ketone spend the night as phase-transfer catalyst reflux under argon gas for 0.28g, 2.0mmol) preparation title compound.Then reactant is carried out TLC, through the mixture of C salt filtration gained, vacuum concentration is to doing.On silica gel,, obtain 0.38g (86%) (R by flash distillation column chromatography purifying (hexane-ethyl acetate, 3: 1) f=0.18 hexane-ethyl acetate, 3: 1) pale yellow powder of desired compounds: mp 70-74 ℃; Solid can be from ethyl acetate and hexane recrystallization; 1H NMR (300MHz, DMSO-d 6) δ 10.62 (s, 1H, NH), 9.75 (s, 1H, NH), 8.56 (d, J=1.9Hz, 1H, ArH), 8.36 (dd, J=9.1Hz, J=1.9Hz, 1H, ArH), 8.18 (d, J=9.1Hz, 1H, ArH), 7.45-7.42 (m, 2H, ArH), 6.85-6.82 (m, 2H, ArH), 6.25 (s, 1H, OH), 4.17 (d, J=9.5Hz, 1H, CHH a), 3.94 (d, J=9.5Hz, 1H, CHH b), 1.98 (s, 3H, Me), 1.43 (s, 3H, Me); 13C NMR (75MHz, DMSO-d 6) δ 174.6 (C=O), 167.7,154.2,143.3,141.6,132.8,127.4,123.0,122.7 (q, J=33.0Hz), 122.1 (q, J=271.5Hz), 120.1,118.3 (q, J=6.0Hz), 114.6,74.9,73.8,23.8,23.0; IR (KBr) 3364 (OH), 1668 (C=O), 1599,1512 (C=C, Ar), 1457,1415,1351,1323,1239,1150,1046cm -1MS (ESI): m/z 464.1 (M+Na) +C 19H 18F 3N 3O 6The analytical calculation value: C 51.71, H4.11, N 9.52. measured value C 52.33, H 4.40, N 9.01.
[Duane?insert]
SARM compound, the especially external activity of compound VI I show excessive androgen receptors bind affinity (Ki=7.5nM).Use the SARM compound, particularly the zooscopy that carries out of compound V proves, this compound is effectively short male and anabolism on-steroidal medicine.Four groups of rats are used for these research: (1) complete contrast, (2) castrating contrast, the neuter that (3) use compound V (100 μ g/ day) treatment with neuter and (4) of testosterone propionate (100 μ g/ day) treatment.Give testosterone and compound VI I through subcutaneous osmotic pump with constant speed, continue 14 days.
Result of study is shown in Fig. 1.Castrating significantly reduces the weight of short male (for example prostate gland and seminal vesicle) and anabolism (for example musculus levator ani) tissue, but to almost not influence of the weight of animals (BW).The weight that to urge male tissue with the animal of testosterone propionate or compound VI I treatment castrating maintains identical degree.Compound VI I has similar short male activity (being that prostate gland is identical with seminal vesicle weight) with testosterone propionate, but has bigger effectiveness as the anabolism medicine.Compound VI I demonstrates the anabolic activity that is better than testosterone propionate (be about to musculus levator ani and maintain the weight identical with complete control animal, and greater than observed weight in the animal of testosterone treatment) under the dosage of being tested.Test described herein is the interior result of the short male body with anabolic activity (being different short male and anabolism abilities) of tissue selectivity of the on-steroidal part of first proof androgen receptor.
Embodiment 2
On-steroidal part with short male and anabolic activity
In rat, checked in the body of four kinds of new on-steroidal male sex hormones (compound IV, V, VI and VII) and renderd a service and acute toxicity.Experiment in vitro confirm these compounds with high affinity in conjunction with androgen receptor.The structure and the title of four kinds of compounds are as follows:
GTx-014 R＝F
GTx-015 R＝COCH 3
GTx-016 R＝COC 2H 5
GTx-007 R＝NHCOCH 3
Test method
Material. (compound VI I, wherein R is NHCOCH according to route synthetic compound GTx-014 (compound IV), GTx-015 (compound V), GTx-016 (compound VI) and GTx-007 shown in Figure 9 3) the S-isomer and the R-isomer of GTx-014.Testosterone propionate (TP), Liquid Macrogol (PEG300, reagent grade) and neutral buffered formalin (10%w/v) available from Sigma Chemical Company (St Louis, MO).Alzet osmotic pump (2002 type) available from Alaa Corp. (Palo Alto, CA).
Animal. immature male Sprague-Dawley rat, body weight 90-100g, available from Harlan Biosciences (Indianapolis, IN).Animal was remained in 12 hours bright-dark cycles, arbitrarily obtain food and water.The experimentation on animals scheme obtains checking and ratifying of Institutional LaboratoryAnimal Care and Use Committee.
Research and design. rat is divided into 29 (29) groups, every group of 5 animals at random.The treatment group is as described in Table 1.Beginning pharmacological agent the day before yesterday, the animal in 2 to 29 groups is taken out from cage individually, weigh, and with intraperitoneal ketamine/xylazine (87/13mg/kg; About 1mL/kg) anesthesia.(to pinch toe reactionless for pinching) makes marks so that discern in animal ear when appropriateness is anaesthetized.Then, animal is placed on the aseptic platform, cleans their belly and scrotum with beta calmly with 70% ethanol.Along the midline incision scrotum, remove testis, before each testis is removed in operation, with organizing on the sterile suture ligation testis.With aseptic stainless steel wound clip (woundclips) closure procedure wound location, clean this position surely with beta.Animal is revived on aseptic platform (until standing), then, put back in the cage.
Behind the twenty four hours, the animal in 2 to 29 groups is anaesthetized again, with the subcutaneous omoplate district of inserting of one or more Alzet osmotic pump (2002 type) with ketamine/xylazine.In this case, the omoplate district uses aseptic scalper to produce little otch (1cm) through shaving hair and cleaning (the fixed and ethanol of beta).Insert osmotic pump, with aseptic stainless steel wound clip closure of wound.Animal is revived and get back in their cage.Osmotic pump contains the suitable therapeutical agent (providing) that is dissolved in the Liquid Macrogol (PEG300) in table 1.Implanting the day before yesterday, be full of osmotic pump with suitable solution.Monitor animal every day to the acute toxicity sign of pharmacological agent (for example drowsiness, fur is coarse).
After the pharmacological agent 14 days, with ketamine/xylazine anesthetized rat.Then, sacrificed by exsanguination animal under the anesthesia.Through aorta abdominalis puncture sample of blood, drawn, for the usefulness of whole blood cell analysis.Part blood is placed independent test tube, under 12000g centrifugal 1 minute, take out plasma layer and also be frozen in-20 ℃.Take out prostate gland siphonal lobe, seminal vesicle, musculus levator ani, liver,kidney,spleen, lung and heart, reject surrounding tissue, weigh, and put into the bottle that contains 10% neutral buffered formalin.The tissue of preserving is delivered to GTx, and Inc. carries out histopathological analysis.
For data analysis, the weight of all organs is normalized to body weight, and analyzes any statistical significant difference by single factor ANOVA.The weight of prostate gland and seminal vesicle is urged male active index with judging, and musculus levator ani weight is used to estimate anabolic activity.
The result
After the administration 14 days, detected the short male and anabolic activity of the R isomer of the S-isomer of compound GTx-014, GTx-015, GTx-016 and GTx-007 in the castrating rat model and GTx-014.The testosterone propionate of ascending-dose is used as the positive control of anabolism and short male function.
Shown in Fig. 2 and 3, in the rat of castrating, vehicle treatment, because the elimination that endogenous male sex hormone produces, the weight of prostate gland, seminal vesicle and musculus levator ani significantly reduces.Testosterone propionate, a kind of external source administration of urging male and anabolic steroid increases the weight of castrating prostate gland, seminal vesicle and musculus levator ani in the rat in the dose-dependently mode.The R-isomer of GTx-014, and the S-isomer of GTx-015 and GTx-016 does not have influence (data not shown) to the weight of prostate gland, seminal vesicle and the musculus levator ani of neuter.GTx-007 (Fig. 2: S-GTx-007) and GTx-014 (Fig. 3: S-isomer S-GTx-014) causes the dose-dependently of prostate gland, seminal vesicle and musculus levator ani weight to increase.Compare with testosterone propionate, S-GTx-007 shows lower effectiveness and intrinsic activity aspect increase prostate gland and seminal vesicle weight, but is showing bigger effectiveness and intrinsic activity aspect the increase musculus levator ani weight.Particularly, under the dosage that is low to moderate 0.3mg/ day, S-GTx-007 can make the musculus levator ani weight of neuter maintain the level identical with intact animal.Therefore, S-GTx-007 is potent on-steroidal anabolism medicine, has than the few short male activity of testosterone propionate but more anabolic activity.This is to surpass previous remarkable improvement of advocating, because this stimulated muscle growth of compound selective ground and other anabolic action, and prostate gland and seminal vesicle are had little effect.This may especially worry to take place prostate cancer with old man or the prostate cancer progress is relevant.
GTx-014 is lower than the effectiveness of GTx-007, but shows bigger tissue selectivity (among Fig. 2 and 3 relatively to the influence of prostate gland and seminal vesicle).GTx-014 significantly increases musculus levator ani weight, but shows or do not show fully the ability that stimulates prostate gland and seminal vesicle growth (be prostate gland and seminal vesicle weight less than at intact animal or in the animal of testosterone propionate treatment observed 20%) hardly.
The result proves that none weight to body weight or other organ (being liver,kidney,spleen, lung and heart) of test-compound produces remarkably influenced.Dock subject animal and carry out test of diagnostic haematol and visual inspection, also produce any acute toxicity sign without any compound.Importantly, GTx-007 does not suppress the generation of lutropin (LH) or follicle stimulating hormone (FSH) yet under the dosage (dosage that promptly shows maximum anabolic action) of 0.3mg/ day.
In a word, S-GTx-007 demonstrates outstanding anabolic activity in animal, keeps the musculus levator ani weight of removing behind the endogenous male sex hormone.Androgenic major progress of on-steroidal that this discovery representative exploitation treatment is useful and the main improvement (being tissue selectivity and effectiveness) that surmounts previous this type of medicine.With testosterone propionate, a kind of short malely compare with anabolic steroid, S-GTx-014 and S-GTx-007 demonstrate selectivity and synthesize metabolic activity.In fact, the tissue selectivity activity is the superiority of on-steroidal male sex hormone aspect the anabolism related application.
Although similar in structure and external functionally active, the S-isomer of compound GTx-014, GTx-015, GTx-016 and GTx-007 is demonstrating sizable difference aspect their activity in vivo.GTx-007 has the most effective short male and anabolic activity in animal, its anabolic activity is higher than the anabolic activity of testosterone propionate.GTx-014 shows low short male level of activity, but anabolic activity is similar to testosterone propionate.On the contrary, GTx-015 and GTx-016 do not produce any short male or anabolic activity in vivo.
These studies show that, two members (GTx-014 and GTx-007 are respectively Compound I I and compound V) that find new class SARM (SARMS) show potent anabolic action (for example muscle growth) and less short male activity (for example prostate gland growth).This new class medicine has some non-selective androgenic advantages that exceed, the potential treatment that comprises the fertility of regulating masculinity and femininity, erythropoiesis, osteoporosis, sexual desire is used, and the potential treatment in suffering from the high-risk male sex of prostate cancer or prostate cancer is used.
In addition, Fig. 7 and 8 has proved GTx-014 and the GTx-007 influence to rat LH and FSH level.These results further prove, because these new SARMs are to the Different Effects of reproductive hormone, thereby show their tissue specificity pharmacologically active.In Fig. 7, under the dosage more than or equal to 0.3mg/ day, in the neuter with TP and GTx-014 treatment, the LH level significantly is lower than the LH level of untreated animal (i.e. castrating contrast).Yet, before observing the remarkable reduction of LH level, need the more GTx-007 of high dosage (being 0.5mg/ day or higher).Therefore, GTx-007 does not suppress the LH level under the dosage that can cause maximum musculus levator ani growth-stimulating.In Fig. 8,, significantly be lower than the FSH level of untreated animal (i.e. castrating contrast) with the FSH level in the neuter of GTx-014 treatment in 0.5mg/ day or more under the high dosage.Similarly, in animal, observe lower FSH level with the TP treatment.Yet only just observing this difference under the dosage of 0.75mg/ day is significance.Under any dosage of being tested, obviously be different from the FSH level of untreated animal with FSH level in the animal of GTx-007 treatment.Therefore, GTx-007 does not suppress the FSH level under the dosage that can cause maximum musculus levator ani growth-stimulating.
Table 1. animal groups and test design
Group number Castration whether? Medicine Dosage Number of animals
1 Not Do not have Do not have 5
2 Be Do not have Carrier only 5
3 Be Testosterone propionate 0.1mg/ day 5
4 Be Testosterone propionate 0.3mg/ day 5
5 Be Testosterone propionate 0.5mg/ day 5
6 Be Testosterone propionate 0.75mg/ day 5
7 Be Testosterone propionate 1.0mg/ day 5
8 Be R-GTx-014 1.0mg/ day 5
9 Be R-GTx-014 0.1mg/ day 5
10 Be R-GTx-014 0.3mg/ day 5
11 Be R-GTx-014 0.5mg/ day 5
12 Be R-GTx-014 0.75mg/ day 5
13 Be R-GTx-014 1.0mg/ day 5
14 Be R-GTx-015 0.1mg/ day 5
15 Be R-GTx-015 0.3mg/ day 5
16 Be R-GTx-015 0.5mg/ day 5
17 Be R-GTx-015 0.75mg/ day 5
18 Be R-GTx-015 1.0mg/ day 5
19 Be R-GTx-016 0.1mg/ day 5
20 Be R-GTx-016 0.3mg/ day 5
21 Be R-GTx-016 0.5mg/ day 5
22 Be R-GTx-016 0.75mg/ day 5
23 Be R-GTx-016 1.0mg/ day 5
24 Be R-GTx-007 0.1mg/ day 5
25 Be R-GTx-007 0.3mg/ day 5
26 Be R-GTx-007 0.5mg/ day 5
27 Be R-GTx-007 0.75mg/ day 5
28 Be R-GTx-007 1.0mg/ day 5
29 Be Do not have Carrier only 5
Embodiment 3
The pharmacokinetics of GTx-007 in dog
In beagle, characterized S-GTx-007, a kind of pharmacokinetics of new SARM (SARM).Use four treatments, phase cross-over design all around under study for action, relate to six beagles altogether, each three of male and female.In the order of random assignment, each animals received is the solution of 3mg/kg IV dosage, 10mg/kg IV dosage, 10mg/kg PO dosage and the capsule of 10mg/kg PO dosage.The clean-up time that one week was arranged between treatment.After giving medicine, collect plasma sample until 72 hours.HPLC methods analyst blood plasma S-GTx-007 concentration with authentication.Use non-chamber model method to measure clearance rate (CL), distribution volume (Vss), transformation period (T 1/2) and other pharmacokinetic parameter.The result shows that after the IV administration, S-GTx-007 is from the terminal T of dog plasma removing 1/2About 4 hours, CL was 4.4mL/min/kg.Fig. 4,5 and 6 shows the plasma concentration-time curve give S-GTx-007 behind intravenous solution, oral liquid and the oral capsule respectively.Pharmacokinetics is dosage and sex dependent/non-dependent.The oral administration biaavailability of S-GTx-007 is different and different according to formulation, and the mean value of solution and capsule is respectively 38% and 19%.Therefore, S-GTx-007 shows the medium transformation period, slowly eliminates and medium bioavailability in beagle, but determines that it is first of tissue selective androgen receptor conditioning agent of the oral biological utilisation of new class.
Embodiment 4
The HPLC of GTx-007 analyzes
Develop anti-phase high pressure liquid chromatography (HPLC) experiment, with the GTx-007 concentration in the quantitative dog plasma.Obtain the dog blood sample through venipuncture, under 1000g centrifugal 15 minutes.With the sample chilled storage at-20 ℃ until analysis.Each sample that thaws rapidly, and get sample aliquot (0.5ml) and go out crest with interior mark (2 μ l, the 200 μ g/ml CM-II-87 aqueous solution).1ml acetonitrile sample aliquot is added in the sample with the precipitation plasma proteins.Behind the vortex sample, under 1000g centrifugal 15 minutes.Supernatant liquor is poured in the glass extracting tube gently, added the 7.5ml ethyl acetate.To extract under the mixture room temperature and place 20 minutes, during this period the vortex several times.Then, centrifugal sample is 10 minutes under 1000g, takes out in the organic phase and the tapered bottom Glass tubing of packing into.Under nitrogen, evaporate organic phase.With 200 μ l moving phases (35: 65 acetonitriles: water) prepare sample again, and be transferred in the automatic sampler bottle of HPLC injection (Waters 717 plus autosampler, Waters Corp., Milord, MA).The moving phase such as degree such as grade of 35% in the water (v/v) acetonitrile is pumped into (510 types, Waters Corp.) with the flow velocity of 1ml/min.Stationary phase is C18 reversed-phase column (Novapak C18,3.9 * 150mm).With UV detector (486 type absorption photometric detectors, Waters Corp.) at 270nm monitoring analysis thing.The retention time of GTx-007 and CM-II-87 was respectively 11.1 and 16.9 minutes.Collect chromatographic data, and use the Millenium software analysis.By comparing the GTx-007 plasma concentration of determining in each sample with calibration curve.Draw calibration curve by the GTx-007 that in dog plasma, adds known quantity.The final concentration of GTx-007 is 0.08,0.2,0.4,2,4,10 and 20 μ g/ml in the dog plasma sample that the making calibration curve uses.Calibration curve is a straight line in this concentration range, and relation conefficient (r2) is 0.9935 or bigger.In a few days and in the daytime the variation coefficient of standard is from 7.9% of 6.4% to the 20 μ g/ml of 0.08 μ g/ml.
Measure fusing point on the Thomas-Hoover capillary melting point apparatus, fusing point is uncorrected.On Perkin Elmer System 2000 FT-IR, write down infrared spectra.At Autopol IIIAutomatic Polarimeter (Rudolph Research Model III-589-10, Fairfield, New Jersey) goes up and measures opticity.On Bruker AX 300 spectrometers, obtain proton and carbon-13 nmr (for 1H and 13C be respectively 300 and 75MHz).Chemical displacement value is reported as with respect to 1,000,000/(δ) of tetramethylsilane (TMS).Spectral data is consistent with specified structure.On Bruker-HP Esquire LC System, measure mass spectrum.By AtlanticMicrolab Inc. (Norcross GA) carries out ultimate analysis, measured value theoretical value 0.4% in.(Milwaukee carries out conventional thin-layer chromatography (TLC) on WI) for silica gel 60 F 254,20 * 20cm, Aldrich ChemicalCompany Inc. at aluminium plate silica gel.On silica gel (Merck, 60 grades, 230-400 order, 60), carry out flash chromatography.By dry tetrahydrofuran (THF) with the sodium Metal 99.5 distillation.By using P 2O 5Distill and dry acetonitrile (MeCN) and methylene dichloride (CH 2Cl 2).

Claims (35)

1. have the interior SARM compound of urging male and anabolic activity of body of the on-steroidal part of androgen receptor, it is expressed from the next:
Figure A2005100674950002C1
Wherein
X is O;
Z is NO 2, CN, COR or CONHR;
Y is I, CF 3, Br, Cl or SnR 3
R is alkyl or OH; And
Q is a halogen.
2. the SARM compound of claim 1, wherein Z is NO 2
3. the SARM compound of claim 1, wherein Y is CF 3
4. the SARM compound of claim 1, wherein Q is F.
5. the SARM compound of claim 1, wherein Z is NO 2, Y is CF 3, and Q is F.
6. pharmaceutical composition, it comprises interior SARM (SARM) compound and pharmaceutically acceptable carrier, thinner or the salt of urging male and anabolic activity of body of the on-steroidal part with androgen receptor of significant quantity, and described compound is represented by the structure of formula (I):
Figure A2005100674950002C2
Wherein
X is O;
Z is NO 2, CN, COR or CONHR;
Y is I, CF 3, Br, Cl or SnR 3
R is alkyl or OH; And
Q is a halogen.
7. the pharmaceutical composition of claim 6, wherein Z is NO 2
8. the pharmaceutical composition of claim 6, wherein Y is CF 3
9. the pharmaceutical composition of claim 6, wherein Q is F.
10. the pharmaceutical composition of claim 6, wherein Z is NO 2, Y is CF 3, and Q is F.
11. SARM compound and androgen receptor bonded method, it comprises makes the interior short male step that contacts with SARM (SARM) compound of anabolic activity of this androgen receptor and the body of the on-steroidal part with androgen receptor, the amount of described SARM compound effectively makes this SARM compound combine with this androgen receptor, and wherein said compound is represented 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 or SnR 3
R is alkyl or OH; And
Q is a halogen.
12. the method for claim 11, wherein Z is NO 2
13. the method for claim 11, wherein Y is CF 3
14. the method for claim 11, wherein Q is F.
15. the method for claim 11, wherein Z is NO 2, Y is CF 3, and Q is F.
16. have the interior purposes of SARM compound in medication preparation of urging male and anabolic activity of body of the on-steroidal part of androgen receptor, described medicine is used for regulating experimenter's spermatogeny, and wherein said compound is represented by the structure of formula (I):
Figure A2005100674950004C1
Wherein
X is O;
Z is NO 2, CN, COR or CONHR;
Y is I, CF 3, Br, Cl or SnR 3
R is alkyl or OH; And
Q is a halogen.
17. the purposes of claim 16, wherein Z is NO 2
18. the purposes of claim 16, wherein Y is CF 3
19. the purposes of claim 16, wherein Q is F.
20. the purposes of claim 16, wherein Z is NO 2, Y is CF 3, and Q is F.
21. have the interior purposes of SARM (SARM) compound in medication preparation of urging male and anabolic activity of body of the on-steroidal part of androgen receptor, described medicine is used for realizing in hormonotherapy the change of the androgen-dependent patient's condition, and wherein said compound is represented 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 or SnR 3
R is alkyl or OH; And
Q is a halogen.
22. the purposes of claim 21, wherein Z is NO 2
23. the purposes of claim 21, wherein Y is CF 3
24. the purposes of claim 21, wherein Q is F.
25. the purposes of claim 21, wherein Z is NO 2, Y is CF 3, and Q is F.
26. have the interior purposes of SARM (SARM) compound in medication preparation of urging male and anabolic activity of body of the on-steroidal part of androgen receptor, the change that described medicine is used to realize the androgen-dependent patient's condition suffers from the experimenter of hormone related conditions with treatment, and wherein said compound is represented 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 or SnR 3
R is alkyl or OH; And
Q is a halogen.
27. the purposes of claim 26, wherein Z is NO 2
28. the purposes of claim 26, wherein Y is CF 3
29. the purposes of claim 26, wherein Q is F.
30. the purposes of claim 26, wherein Z is NO 2, Y is CF 3, and Q is F.
31. have the interior purposes of SARM (SARM) compound in medication preparation of urging male and anabolic activity of body of the on-steroidal part of androgen receptor, described medicine is used for the treatment of the experimenter who suffers from prostate cancer, and wherein said compound is represented 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 or SnR 3
R is alkyl or OH; And
Q is a halogen.
32. the purposes of claim 31, wherein Z is NO 2
33. the purposes of claim 31, wherein Y is CF 3
34. the purposes of claim 31, wherein Q is F.
35. the purposes of claim 31, wherein Z is NO 2, Y is CF 3, and Q is F.
CN 200510067495 2000-08-24 2001-08-23 Selective androgen receptor modulators and methods of use thereof Pending CN1736981A (en)

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