WO2010118287A1 - Modulateurs sélectifs du récepteur aux androgènes - Google Patents

Modulateurs sélectifs du récepteur aux androgènes Download PDF

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Publication number
WO2010118287A1
WO2010118287A1 PCT/US2010/030480 US2010030480W WO2010118287A1 WO 2010118287 A1 WO2010118287 A1 WO 2010118287A1 US 2010030480 W US2010030480 W US 2010030480W WO 2010118287 A1 WO2010118287 A1 WO 2010118287A1
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Prior art keywords
alkyl
independently selected
phenyl
hydrogen
haloalkyl
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PCT/US2010/030480
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WO2010118287A8 (fr
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Chris P. Miller
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Radius Health, Inc.
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Publication of WO2010118287A1 publication Critical patent/WO2010118287A1/fr
Publication of WO2010118287A8 publication Critical patent/WO2010118287A8/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • Androgen signaling is mediated through the androgen receptor (AR) and is a nuclear signaling pathway of tremendous importance in mammals.
  • AR androgen receptor
  • this critical hormone signaling pathway affects a large number of non-sexual tissues including, bone, muscle, CNS, liver, etc.
  • testosterone and dihydrotestosterone are the primary ligands that mediate AR- signaling. Both are high affinity ligands for AR, with dihydrotestosterone having somewhat higher affinity.
  • Testosterone is converted to dihydrotestosterone through the action of 5 ⁇ -reductase enzymes and is converted to 17 ⁇ -estradiol (potent endogenous estrogen) through the action of P-450 aromatase enzymes.
  • AR signaling is mediated by binding of an AR ligand to AR in the cellular cytosol, homodimerization of two AR receptors and nuclear location of the ligand bound dimer to the cell nucleus where the complex associates with various coactivators as well as Androgen Response Elements (palindrome-like sequences of DNA) which serve as activation sites for certain AR-mediated genes.
  • both sexual and non-sexual, androgens such as testosterone and dihydrotestosterone have a number of potentially desirable actions as well as non-desirable actions depending on the particular individual's age, sex, therapeutic need, etc.
  • certain positive consequences of AR-agonist signaling can be generalized as including increased bone mineral density and a corresponding reduction of risk of bone fractures.
  • androgen supplementation can be very valuable in the prevention or treatment of osteoporosis where the osteoporosis might originate from any number of different causes, such as corticosteroid induced osteoporosis and age-related osteoporosis (e.g. postmenopausal).
  • males and females respond to agonist supplementation with an increase in muscle mass and very often a decrease in fat mass.
  • This is beneficial in a very large number of treatment modalities.
  • Other muscle- wasting disorders such as muscular dystrophy in its many forms as well as related disorders can also be treated to advantage with androgens.
  • the increase in muscle mass with concomitant reduction in fat mass associated with anabolic androgen action has additional health benefits for many men and women including potentially increased sensitivity to insulin.
  • Androgen supplementation is also associated with reduction of high triglycerides, though there is a general correlation with androgen use and decreased HDL levels and in some cases, increased LDL levels.
  • Androgen antagonists have been used in treating prostate cancer, where blockade of androgen signaling is desired whereas some androgens agonists (e.g. dihydrotestosterone) stimulate the hypertrophy of prostate tissue and may be a causative factor in prostate cancer.
  • Androgen agonist activity is often associated with stimulation of benign prostate hyperplasia, a disease characterized by an enlarged prostate often accompanied by discomfort and difficulty in urination due to blockage of the urethra.
  • androgen antagonists have efficacy in the reduction of the size of the prostate and the corresponding symptoms of benign prostate hyperplasia, though it is much more common to use a 5 ⁇ -reductase inhibitor (e.g. finasteride) as such inhibitors do not decrease androgen signaling systemically to the same extent as a typical anti-androgen (e.g. bicalutamide), but rather reduce androgen drive more site specifically to where testosterone to DHT conversion occurs such as the prostate and scalp.
  • Androgen antagonists also find utility in the treatment of hirsutism in women as well as the treatment of acne. Androgens are generally contraindicated in conditions that are treated with androgen antagonists since they can exacerbate the symptoms that are being treated.
  • an androgen would retain the benefits of androgen agonists while minimizing the stimulatory effects on the prostate in males as well as some of the other untoward effects of androgens including masculinization of women and increase in acne in both sexes.
  • Androgens that demonstrate tissue selective effects compared to the benchmarks testosterone and/or dihydrotestosterone are typically referred to as androgen receptor modulators or more often, selective androgen receptor modulators (SARMs).
  • SARMs selective androgen receptor modulators
  • this invention describes a compound of formula I
  • R x is CN, Cl, Br, NO 2 or R xl ;
  • R y is hydrogen, CH 3 , CF 3 , or halogen
  • R xI is a 5 member heteroaryl, said heteroaryl selected from ⁇ r O o-V
  • R' is hydrogen or optionally Ci-C 2 alkyl, CF 3 , or halogen; or R x and R y together with the phenyl group to which they are attached form a 5 member aromatic ring selected from:
  • each R" is independently hydrogen or optionally CF 3 , or C)-C 2 alkyl
  • A is a bond or a 5- or 6- member heteroaryl group wherein said 5- or 6- member heteroaryl is substituted with hydrogen and optionally up to two substituents independently selected from Ci -3 alkyl, CN, Ci -3 haloalkyl or halogen;
  • B is a phenyl, Ci -6 alkyl, Ci -6 haloalkyl, 5- or 6-member heteroaryl or bicyclic heteroaryl; each R a is independently selected from Ci -4 alkyl (optionally substituted with from 1-2 substituents independently selected from CN, OH or 5 member heteroaryl), 5-member heteroaryl, CN, - N(R b )C(0)0Ci -6 alkyl, - N(R b )C(O)OPhenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, C ]-3 alkyl, and OCi.
  • each R b and R b ' is independently selected from hydrogen, Ci -3 alkyl and Ci -3 haloalkyl; n is O, 1, 2, or 3; n' is O or l ; n" is O or 1 ;
  • Ri, R 2 , R 5 , R 6 , R 7 and Rg are each independently selected from hydrogen, Ci -3 alkyl, Ci -3 haloalkyl, OR 3 and phenyl;
  • R 9 is hydrogen, Ci -3 alkyl or OR 3 ; provided that at least one of Ri , R 2 , R 5 , R 6 , R 7 , R 8 or R 9 is OR 3 ; each R 3 is independently selected from hydrogen, Ci -4 alkyl, Ci -4 haloalkyl, C 2-4 hydroxylalkyl, benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1-3 substituents independently selected from halogen, Ci -3 alkyl, S(O) 0-2 Ci -3 alkyl, S(O) 0-2 phenyl, 0-C 1-6 alkyl, OCF 3 ), C(O)-Ci-I 0 alkyl, SO 3 -, PO 3 -, SO 2 NRbRb' and C(O)phenyl;
  • D and E are each independently C or N;
  • Rio and Rn are at each and every occurrence independently selected from hydrogen, Cj -3 alkyl, Ci -3 haloalkyl, CN or halogen; p is O, 1 or 2; q is O, 1 or 2; and
  • R 4 is H, C] -4 alkyl or Ci -4 haloalkyl; or pharmaceutically acceptable salts thereof.
  • this invention describes a compound of formula I wherein:
  • R x is CN, Cl, Br, NO 2 or R xl ;
  • Ry is hydrogen, CH 3 , CF 3 , or halogen
  • R x is a 5 member heteroaryl, said heteroaryl selected from
  • R' is hydrogen or optionally Ci-C 2 alkyl, CF 3 , or halogen
  • each R" is independently hydrogen or optionally CF 3 , or Ci-C 2 alkyl
  • A is a bond or a 5- or 6- member heteroaryl group wherein said 5- or 6- member heteroaryl is substituted with hydrogen and optionally up to two substituents selected from Ci -3 alkyl, CN, Ci -3 haloalkyl or halogen
  • B is a phenyl, Ci -6 alkyl, Ci -6 haloalkyl, 5- or 6-member heteroaryl or bicyclic heteroaryl
  • each R a is independently selected from Ci -4 alkyl (optionally substituted with from 1-2 substituents independently selected from CN, OH or 5 member heteroaryl), 5-member heteroaryl, CN, - N(R b )C(O)OCi -6 alkyl, - N(R b )C(O)OPhenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH,
  • R] R 2, R 5, R 6, R ? and Rg are each independently selected from hydrogen, Ci -3 alkyl, Ci -3 haloalkyl, OR 3 and phenyl;
  • R 9 is hydrogen, Ci -3 alkyl or OR 3 ; provided that at least one of Ri, R 2 , R 5 , R 6 , R 7 , Rs or R 9 is OR 3 ; each R 3 is independently hydrogen, Cj -4 alkyl, Ci -4 haloalkyl, C 2-4 hydroxylalkyl, benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1-3 substituents independently selected from halogen, Ci -3 alkyl, S(O) 0-2 Ci -3 alkyl,
  • Rio and Ri i are at each and every occurrence independently selected from hydrogen, Ci -3 alkyl, Ci -3 haloalkyl, CN or halogen;p is O, 1 or 2; q is O, 1 or 2; and
  • R 4 is H, C 14 alkyl or C] -4 haloalkyl; or pharmaceutically acceptable salts thereof.
  • R x is CN
  • R y is CF 3 or Cl.
  • D is
  • E is C.
  • both D and E are C.
  • both D and E are C and are connected by a double bond.
  • both D and E are C and are connected by a single bond.
  • Rio and Ri i are hydrogen at each occurrence.
  • Rio is hydrogen at each occurrence and Ri i is CH 3 or CF 3 at least at one occurrence.
  • R x is CN and R y is CF 3 or Cl.
  • R 4 is hydrogen or CH 3 . In certain embodiments of this invention, for the compound of formula I, R 4 is hydrogen.
  • R x is CN
  • R y is CF 3 or Cl
  • R 4 is hydrogen
  • A is a 5 member heteroaryl.
  • A is a 5 member heteroaryl selected from the following group of 5 member heteroaryls:
  • each R" is independently hydrogen, CF 3 , or Ci -C 2 alkyl
  • R y is CF 3 or Cl
  • R 4 is hydrogen and A is .
  • B is phenyl
  • R a is as defined previously in I.
  • R x is
  • R a is CN, OH, F or Cl.
  • R x is
  • R x is
  • R a is CN, OH, F or Cl.
  • Ri or R 2 is OR 3 .
  • R 5 or R 6 is OR 3 .
  • R 7 or Re is OR 3 and R 9 is hydrogen.
  • R 9 is hydrogen or methyl.
  • Ri is OR 3 , R 2 is hydrogen, n' is O and n" is O and R 9 is hydogen.
  • Ri and R 2 are each hydrogen, R 5 is OR 3 and R 6 is hydrogen, R 9 is hydrogen and n' ' is 0.
  • R 3 is hydrogen.
  • R x is hydrogen.
  • R x is CN, R y is CF 3 or Cl, R 4 is hydrogen, A is ' -J ° 1 T ''" , B i is a , wherein R a is CN, OH, F or Cl and R 1 or R 2 is OR 3 , either R] or R 2 is methyl, n' and n" are each 0 and R9 is hydrogen or methyl.
  • R x is CN, R y is CF 3 or Cl, R 4 is hydrogen, A is ' -J ° 1 T ''" , B i is a , wherein R a is CN, OH, F or Cl and R 1 or R 2 is OR 3 , either R] or R 2 is methyl, n' and n" are each 0 and R9 is hydrogen or methyl.
  • R x is CN, R y is CF 3 or Cl, R 4 is hydrogen, A is ' -J ° 1 T ''" , B i is
  • R a is CN, OH, F or Cl and R 1 or R 2 is OR 3 , either R 1 or R 2 is methyl, n' and n" are each 0 and R 9 is hydrogen or methyl and R 3 is hydrogen.
  • R x is is, CN, OH, F or Cl and Ri or R 2 is OR 3 , either Ri or R 2 is methyl, n' and n" are each O, R 9 is hydrogen or methyl and R 3 is hydrogen.
  • R x is CN, Cl, Br, NO 2 or R x] ;
  • R y is CH 3 , CF 3 , or halogen;
  • R x i is a 5 member heteroaryl, said heteroaryl selected from
  • N N N R' is hydrogen, Ci-C 2 alkyl, CF 3 , or halogen
  • R x and R y together with the phenyl group to which they are attached form a 5 member aromatic ring selected from: wherein: each R" is independently hydrogen, CF 3 , or C]-C 2 alkyl;
  • A is a bond or a 5- or 6- member het ⁇ roaryl group; each R a is independently selected from Ci -4 alkyl (optionally substituted with from 1-2 CN, OH or 5 member heteroaryl), 5-member heteroaryl, CN, - N(R b )C(O)OC 1-6 alkyl, - N(R b )C(O)OPhenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, Ci -3 alkyl, and OC 1-3 alkyl), - N(R b )C(O)C 1-6 alkyl, - N(R b )C(O)Phenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, C 1-3 alkyl, and OCj -3 alkyl), NRbRb-, Ci -4 haloalkyl
  • Ci -3 haloalkyl is O, 1, 2, or 3;
  • Ri and R 2 are each independently selected from hydrogen, Ci -3 alkyl, C 1-3 haloalkyl and phenyl;
  • R 3 is hydrogen, Ci -4 alkyl, Ci -4 haloalkyl, C 2-4 hydroxylalkyl, benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1-3 substituents independently selected from: halogen, Ci -3 alkyl, S(O) O-2 C] -3 alkyl, S(O) 0-2 phenyl, 0-C 1-6 alkyl, OCF 3 ), C(O)-C 1-6 alkyl and C(O)Phenyl;
  • D and E are each independently C or N;
  • R 1O and R 11 are at each and every occurrence independently selected from hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, CN or halogen;
  • R 4 is H, Ci -4 alkyl or Ci -4 haloalkyl; or pharmaceutically acceptable salts thereof.
  • A is a 5 member heteroaryl group
  • A is a 5 member heteroaryl group selected from the group consisting of:
  • each R" is independently hydrogen, CF 3 , or Ci-C 2 alkyl.
  • R x may be CN
  • R y is CF 3 or Cl. In some embodiments, for the compound of formula Ia, R x is CN and R y is Cl.
  • D and E are both C.
  • D and E are both C
  • p and q are each 2 and each Rio and Rn are independently at each occurrence selected from hydrogen, CH 3 or CF 3 .
  • p and q are each 1, and each Rio and Rn are independently at each occurrence selected from hydrogen, CH 3 or CF 3 .
  • R 8 is OH, OMe, OCF 3 , CN, SO 2 CH 3 , or halogen and n is 1.
  • R a is 4'-Fl or 4'-Cl.
  • R a is 4'-OH.
  • R 8 is 4'-CN. In certain embodiments of this invention, for the compound of formula Ia, n is O.
  • R 4 is H, CH 3 or CH 2 CF 3 .
  • R 4 is H.
  • Ri and R 2 are each independently H, CH 3 , or CF 3 , and at least one of Ri and R 2 is not H.
  • Ri is H and R 2 is CH 3 .
  • Rj is CH 3 and R 2 is H.
  • Ri is H
  • R 2 is CF 3
  • Rj is CF 3 and R 2 is H.
  • R 3 is H.
  • R x is CN, R y is Cl, A is D and E are both C, p and q are each 2, and each Rio and Rn are independently at each occurrence selected from hydrogen, CH 3 or CF 3 .
  • R a is selected from halogen, CN, OCH 3 and OH, n is 0 or 1, Ri is H or CH 3 , R 2 is H or CH 3 , R 3 is H, R 4 is H, wherein at least one of Ri and R 2 is not H.
  • R x is CN, R,, is CL A is , D and E are both C and connected by a double bond, p and q are each 1, and each Rio and Rn are independently at each occurrence selected from hydrogen, CH 3 or CF 3 .
  • R a is selected from halogen, CN, OCH 3 and OH, n is O or 1 , Ri is H or CH 3 , R 2 is H or CH 3 , R 3 is H, R 4 is H, wherein at least one of Rj and R 2 is not H.
  • this invention describes a compound of formula Ib or Ic
  • R y is hydrogen, CF 3 or Cl; each R 8 is independently selected from Ci ⁇ alkyl (optionally substituted with from 1-2 substituents independently selected from CN, OH or 5 member heteroaryl), 5-member heteroaryl, CN, - N(R b )C(O)OCi -6 alkyl, - N(R b )C(O)OPhenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, C1. 3 alkyl, and OQ.
  • Ri and R 2 are each independently selected from hydrogen, C] -3 alkyl, Ci -3 haloalkyl and phenyl;
  • R 3 is hydrogen, C] -4 alkyl, Ci -4 haloalkyl, C 2-4 hydroxylalkyl, benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1 -3 substituents independently selected from: halogen, Cj -3 alkyl, S(0)o- 2 Ci_ 3 alkyl, S(0)o- 2 phenyl, O-Ci- 6 alkyl, OCF 3 ), Ci -6 acyl, and benzoyl;
  • R 4 is H, C i- 4 alkyl or Ci -4 haloalkyl
  • Rio and Rn are at each and every occurrence independently selected from hydrogen, Cj -3 alkyl, Ci -3 haloalkyl, CN or halogen; or pharmaceutically acceptable salts thereof.
  • R y is CF 3 or Cl.
  • Rio and Rn are each independently selected from hydrogen, CH 3 or CF 3 .
  • Ri and R 2 are each independently selected from hydrogen and CH 3 .
  • R 4 is hydrogen
  • each R a is independently selected from 5-member heteroaryl, CN, - N(R b )C(O)OCi -6 alkyl, - N(R b )C(O)OPhenyl (wherein said phenyl is optionally substituted with from 1 -3 substituents independently selected from CN, halogen, OH, Ci -3 alkyl, and OCi -3 alkyl), - N(R b )C(O)Cj -6 alkyl, - N(R b )C(O)Phenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, Ci -3 alkyl, and OCi -3 alkyl), C M haloalkyl, halogen, OH, OC 1-3 alkyl, OC 1-3 haloalkyl and S(O) 0-2 Ci
  • R 3 is hydrogen.
  • R y is CF 3 or Cl
  • Rio and Rn are each independently selected from hydrogen, CH 3 or CF 3 .
  • R y is CF 3 or Cl
  • Rio and Rn are each independently selected from hydrogen, CH 3 or CF 3 and R 4 is hydrogen.
  • R y is CF 3 or Cl
  • Rio and Rn are each independently selected from hydrogen, CH 3 or CF 3
  • R 4 is hydrogen and each R a is independently selected from 5 -member heteroaryl, CN, - N(R b )C(O)OCi -6 alkyl, - N(R b )C(O)OPhenyl (wherein said phenyl is optionally substituted with from 1 -3 substituents independently selected from CN, halogen, OH, Ci -3 alkyl, and OC 1-3 alkyl), - N(R b )C(O)Ci_ 6 alkyl, - N(R b )C(O)Phenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, Ci -3 alkyl, and OCi -3 alkyl), Ci -4 haloalkyl
  • R b and R b > are each independently selected from hydrogen, Ci -3 alkyl and Ci- 3 haloalkyl; and n is O, 1 or 2.
  • R 3 is hydrogen. In some embodiments of this invention, the compound of formula I, Ia, Ib or
  • Ic is selected from the following list.
  • the compound names in the list were generated with the assistance of ChemDraw ® versions 8.0, 9.0 and/or 11.0 (CambridgeSoft Corporation, 100 CambridgePark Drive, Cambridge, MA 02140 USA)).
  • ChemDraw ® versions 8.0, 9.0 and/or 11.0 (CambridgeSoft Corporation, 100 CambridgePark Drive, Cambridge, MA 02140 USA)
  • the stereochemistry at a chiral center is not defined in the compound name this indicates that the sample prepared contained a mixture of isomers at this center.
  • this invention describes a compound selected from one of the following:
  • the invention also relates to pharmaceutical compositions comprising a compound of formula I, Ia, Ib or Ic, or any of the structural embodiments described herein and at least one pharmaceutically acceptable excipient.
  • the invention also provides a method of modulating an androgen receptor in a cell, comprising the administration of a compound to said cell wherein said compound has structural formula I, Ia, Ib or Ic, or any of the structural embodiments described herein, or a pharmaceutically acceptable salt thereof.
  • This invention provides a method of identifying a compound capable of modulating an androgen receptor comprising contacting a cell expressing an androgen receptor with a compound according to formula I, Ia, Ib or Ic, and monitoring the effect of the compound on the cell.
  • This invention also provides a method of treating (e.g., preventing, or ameliorating the symptoms associated with, or reducing the incidence of, reducing the pathogenesis of, facilitating the recovery from or delaying the onset of) a disease, syndrome, illness, or symptom associated with insufficient androgen levels in a mammal in need thereof, wherein said method comprises the administration to said mammal of an effective amount of a compound of formula I, Ia, Ib or Ic, or any one of the structural embodiments described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I, Ia, Ib, or Ic, or one of the structural embodiments described herein, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • a method of treating e.g., preventing, or ameliorating the symptoms associated with, or reducing the incidence of, reducing the pathogenesis of, facilitating the recovery from or delaying the onset of
  • the mammal is a human.
  • this invention provides a method of treating (e.g., preventing, or ameliorating the symptoms associated with, or reducing the incidence of, reducing the pathogenesis of, facilitating the recovery from or delaying the onset of) sarcopenia, frailty, multiple sclerosis, osteoporosis, anemia, cognitive impairment, cachexia, muscular dystrophy, weak appetite, low body weight, anorexia nervosa, acne, seborrhea, polycystic ovarian syndrome, hair loss, AIDs wasting, chronic fatigue syndrome, short stature, low testosterone levels, diminished libido, benign prostate hypertrophy, infertility, erectile dysfunction, vaginal dryness, premenstrual syndrome, postmenopausal symptoms, female hormone replacement therapy, male hormone replacement therapy, depression, Type II diabetes, mood disorders, sleep disorders, memory disorders, neurodegenerative disorders, Alzheimer's dementia, attention deficit disorder, senile dementia,
  • this invention describes a method of treating (e.g., preventing, or ameliorating the symptoms associated with, or reducing the incidence of, reducing the pathogenesis of, facilitating the recovery from or delaying the onset of) prostate cancer, breast cancer, endometrial cancer, hepatocellular cancer, lymphoma, multiple endocrine neoplasia, vaginal cancer, renal cancer, thyroid cancer, testicular cancer, leukemia, and ovarian cancer in a mammal in need thereof comprising the administration to said mammal of a compound according to a structure of formula I, Ia, Ib, or Ic, or one of the structural embodiments described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of structural formula I, Ia, Ib, or Ic, or one of the structural embodiments described herein including pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient.
  • the mammal is a human.
  • alkenyl refers to a hydrocarbon backbone radical, having the number of carbon atoms falling within the specified range.
  • C 2-3 alkenyl means that a hydrocarbon radical is attached that may contain anywhere from 2 to 3 carbon atoms with the remaining valence filled in by hydrogen atoms unless specified otherwise. The term also includes each permutation as though it were separately listed. Thus, C 2-3 alkenyl includes ethenyl, 1-propenyl and 2- propenyl.
  • alkyl refers to both straight and branch chain hydrocarbon radicals, having the number of carbon atoms falling within the specified range.
  • Ci -4 alkyl means that a hydrocarbon radical is attached that may contain anywhere from 1 to 4 carbon atoms with the remaining valence filled in by hydrogen atoms. The definition also includes separately each permutation as though it were separately listed.
  • Ci -2 alkyl includes methyl and ethyl.
  • Ci -3 alkyl includes methyl, ethyl, propyl and 2-propyl.
  • Cj is methyl, ethyl, propyl and 2-propyl.
  • C 4 alkyl includes methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, iso-butyl and tert- butyl.
  • C 1 - 5 alkyl includes methyl, ethyl, 2-propyl, n-butyl, 2-methylbutyl, tert-butyl, n-pentyl, pentan-2-yl, pentan-3-yl, and tert-pentyl, iso-pentyl.
  • halogen refers to a fluorine, chlorine, bromine or iodine radical.
  • haloalkyl refers to an alkyl radical wherein said alkyl radical is the same as defined for the term “alkyl” except that the alkyl radical additionally has from 1 to 5 halogen atoms attached to the alkyl chain.
  • Ci haloalkyl includes
  • C 2 haloalkyl includes -CH 2 F, CHF 2 , CF 3 , - CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CHF 2 , -CF 2 CF 3 and the like.
  • C 1-3 haloalkyl is defined to include -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CHFCF 3 , -CF 2 CF 3 , -CHClCH 3 , - CH 2 CH 2 Cl, -CH 2 CH 2 CF 3 , and the like.
  • Ci -4 haloalkyl is defined to include -CH 2 F, - CHF 2 , -CF 3 , -CH 2 CF 3 , -CHFCF 3 , -CF 2 CF 3 , -CHClCH 3 , -CH 2 CH 2 Cl, -CH 2 CH 2 CF 3 , - CH 2 CH 2 CH 2 CF 3 , CFICICF 2 CH 2 CH 3 , CF 2 CH 2 CH 2 CHF 2 , CH 2 CFI 2 CH 2 CH 2 F, CH 2 CH 2 CH 2 CH 2 Cl, and the like.
  • hydroxy alkyl refers to an alkyl radical wherein said alkyl radical is the same as defined for the term “alkyl” except that the alkyl radical additionally has from 1 or 2 hydroxyl groups attached to the alkyl chain.
  • C 2- 4 hydroxyalkyl includes 2-hydroxyethyl, 2-hydroxypropyl, 2,4-dihydroxybutyl and the like.
  • 5-member heteroaryl refers to a heteroaryl ring system radical wherein said heteroaryl contains at least one heteroatom selected from the groups consisting of N, O and S and up to 3 additional heteroatoms selected from the group consisting of N, O and S.
  • the 5-member rings system is optionally substituted with 1-2 substituents selected from halogen, Ci -2 alkyl, Ci -2 haloalkyl, or CN.
  • the points of attachment of the optional substituent(s) as well as the rest of the molecule maybe selected from any position wherein there is an open valence.
  • 5-member heteroaryls include:
  • 6-member heteroaryl refers to a heteroaryl ring system radical wherein said heteroaryl contains at least one heteroatom selected from N and up to two additional Ns. If not otherwise specified, the 6-member heteroaryl ring is optionally substituted with 1-2 substituents selected from halogen, Ci -2 alkyl, Ci -2 haloalkyl, or CN. The points of attachment of the optional substituent(s) as well as the rest of the molecule maybe selected from any position wherein there is an open valence.
  • 6-membered heteroaryls include:
  • bicyclic heteroaryl refers to a bicyclic fused-ring system wherein at least one of the two rings is substituted with at least one heteroatom selected from N, O and S.
  • the bicyclic heteroaryl ring system contains from 8 to 12 backbone atoms and may contain a total of up to 4 heteroatoms in the backbone.
  • the bicylic heteroaryl ring systems of this invention require that at least one of the two rings is aromatic but the two rings together may be aromatic as well (e.g. quinoline).
  • the compounds of this invention may be present as solids and when so present, may be in an amorphous form or they may be crystalline. When the compounds of this invention are in the crystalline form, they might be present as a single polymorph or a mixture of polymorphs or even as a mixture of amorphous material together with one or more distinct polymorphs - the invention is not limited according to any particular solid or liquid state form.
  • Stereoisomers are compounds which differ only in their spatial arrangement.
  • Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center.
  • “Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable.
  • Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms.
  • "/?” and "S" represent the configuration of substituents around one or more chiral carbon atoms.
  • i?” and “S”' denote the relative configurations of substituents around one or more chiral carbon atoms
  • the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to the other stereoisomers.
  • the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enantiomer over the weight of the enantiomer plus the weight of its optical isomer.
  • the compounds of the invention may be prepared as individual isomers by incorporating or starting with a specific isomer, isomer-specific synthesis or resolution from an isomeric mixture.
  • Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.
  • acid addition salts can be made and this invention includes such acid addition salts.
  • Some representative (non-limiting) acid addition salts include hydrochloride, hydrobromide, hydroiodide, acetate, benzenesulfonate, mesylate, besylate, benzoate, tosylate, citrate, tartrate, sulfate, bisulfate, lactate, maleate, mandelate, valerate, laurate, caprylate, propionate, succinate, phosphate, salicylate, napsylate, nitrate, tannate, resorcinate and the like, including multiprotic salts as well as mixtures of the acid addition salts.
  • this invention also embraces quaternized ammonium salts of those amines. It should be appreciated that N-oxides of amines are also embraced within the definition of the compounds of this invention.
  • compounds of this invention include one or more acid sites such as carboxylic acids, phenols and the like, basic addition salts can be made and this invention includes such basic addition salts.
  • some representative (non-limiting) acidic compounds of this invention may be present as their lithium, sodium, potassium, ammonium, trialkyammonium, calcium, magnesium, barium and the like.
  • solvates can also be present as solvates and such solvates are embraced within the scope of this invention even where not explicitly described.
  • Such solvates are preferably hydrates but can be solvates comprised of other solvents, preferably where those solvents are considered to be non-toxic or at least acceptable for administration to mammals, preferably humans.
  • the solvates can be stoichiometric or non-stoichiometric, singular or in combination.
  • Some exemplary solvates include water, ethanol, acetic acid and the like.
  • the therapeutic utility of these compounds includes "treating" a mammal, preferably a human where treating is understood to include treating, preventing, or ameliorating the symptoms associated with, or reducing the incidence of, reducing the pathogenesis of, facilitating the recovery from or delaying the onset of the syndrome, illness, malady or condition being considered.
  • the compounds of this invention can also be useful in states or conditions where no clear deficit, illness or malady per se is perceived but rather, where a preferred condition, sensation, performance, capability or state is obtainable through therapeutic intervention with a compound of this invention.
  • the compounds of this invention when used as therapeutics can be administered by any method known to one of skill in the art such as orally, bucally, intravenously, subcutaneously, intramuscularly, transdermally, intradermally, intravascularly, intranasally, sublingually, intracranially, rectally, intratumorally, intravaginally, intraperitonealy, pulmonary, ocularly and intratumorally.
  • the term "effective amount” refers to an amount which, when administered in a proper dosing regimen, is sufficient to treat (therapeutically or prophylactically) the target disorder. For example, and effective amount is sufficient to reduce or ameliorate the severity, duration or progression of the disorder being treated, prevent the advancement of the disorder being treated, cause the regression of the disorder being treated, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy.
  • the compounds and compositions of this invention maybe given once daily or with multiple daily doses such as twice per day, three times per day and four times per day.
  • the compound is administered orally where it can be formulated for solid dosage administration or liquid dosage administration.
  • Solid dosage administration can be in the form of a tablet, granule, capsule, pill, pellet, powder and the like.
  • Liquid dosage formulations include syrups, solutions, gels, suspensions, elixirs, emulsions, colloids, oils, and the like.
  • the compounds of this invention may be solids and when present as solids, they maybe of defined particle size. Where the compound of this invention is not particularly water soluble, it is sometimes preferable to administer the compound with a certain particle size - a particle size with a preferred range where the average mean particle size diameter is under 100 microns, or 75 microns, or 50 microns, or 35 microns, or 10 microns or 5 microns.
  • Solid dosage formulations will comprise at least one compound of this invention together with one or more pharmaceutical excipients.
  • excipients include, by way of non-limiting example diluents (monosaccharides, disaccharides and polyhydric alcohols including starch, mannitol, dextrose, sucrose, microcrystalline cellulose, maltodextrin, sorbitol, xylitol, fructose and the like), binders (starch, gelatin, natural sugars, gums, waxes and the like), disintegrants (alginic acid, carboxymethylcellulose (calcium or sodium), cellulose, crocarmellose, crospovidone, microcrystalline cellulose, sodium starch glycolate, agar and the like), acidic or basic buffering agents (citrates, phoshphates, gluconates, acetates, carbonates, bicarbonates and the like), chelating agents (edetic acid, edetate calcium, edetate disodium and the like), preservatives (benzoic acid, chloride, sorbitol, xy
  • the solid dosage formulations of this invention can be prepared in different forms including most commonly, tablets and capsules.
  • the tablets can be formulated by a wide variety of methods known to one of skill in the art including, for example, preparing a dry powder mixture of the drug substance in combination with one or more of the excipients granulating the mixture and pressing to together into a tablet and optionally coating the tablet with an enteric or non-enteric coating.
  • the final coat typically includes a light protective pigment such as titanium oxide and a shellac or wax to keep the tablet dry and stable. While not intending to be limited by theory or example, in some instances it might be preferred to prepare the tablets by wet granulating the drug with one or more of the excipients and then extruding the granulated material.
  • the solid dosage forms of this invention also include capsules wherein the drug is enclosed inside the capsule either as a powder together with optional excipients or as granules containing usually including one or more excipients together with the drug and wherein the granule in turn can be optionally coated, for example, enterically or non-enterically.
  • the solid dosage formulations of this invention are formulated in a sustained release formulation.
  • sustained release formulations are known to those of skill in the art and generally rely on the co-formulation of the drug with one or more matrix forming substances that slow the release of the androgen receptor modulator thus extending the compound's lifetime in the digestive track and thereby extend the compounds half-life.
  • matrix forming substances include hydroxypropyl methylcellulose, carbopol, sodium carboxymethylcellulose and the like.
  • the compounds are formulated for delivery other than via a solid oral dosage form.
  • a pulmonary route of administration typically means that the compound of this invention is inhaled into the lung where it is absorbed into the circulation.
  • Such a route of administration has the advantage of avoiding a first pass liver effect thereby possibly increasing bioavailability as well as decreasing or eliminating undesirable androgen agonist effects on the liver such as increasing liver enzymes and/or decreasing HDL.
  • Formulating a compound of the invention for pulmonary delivery can be accomplished by micronizing the compound of the invention to a very fine size particle, typically with a mean average diameter of less than 20 microns, or less than 10 microns or between 2 and 5 microns.
  • the powder may then be inhaled by itself or more likely mixed with one or more excipients such as lactose or maltose.
  • the powder can then be inhaled in a dry powder inhaling device either once or multiple times per day depending on the particular compound and the patients need.
  • Other types of pulmonary dosage forms are also embraced by this invention.
  • the compound of this invention may be suspended in an aerosolizing medium and inhaled as a suspension through a meter dosed inhaler or a nebulizer.
  • the compounds of this invention can be formulated for transdermal delivery. Effective advantage of these compounds can be taken through a wide variety of transdermal options.
  • the compounds of this invention maybe formulated for passive diffusion patches where they are preferably embedded in a matrix that allows for slow diffusion of the compound into the treated subject's circulation.
  • the compound is preferably dissolved or suspended in solvents including by way of non-limiting examples one or more of ethanol, water, propylene glycol, and Klucel HF.
  • a polymer matrix e.g. acrylate adhesive
  • the transdermal formulations maybe designed to be compatible with alternate transdermal delivery technologies.
  • some transdermal technologies achieve greater and/or more consistent delivery by creating micropores in the skin using radio frequency, heat, ultrasound or electricity.
  • the compounds of this invention can be used with microneedle technology wherein the compound is loaded into or on top of very small needles which due not need to penetrate the dermis to be effective.
  • the compounds of this invention may be employed alone or in combination with other therapeutic agents.
  • the compounds of this invention can be used in combination with anti-lipidemics (statins, fibrates, omega-3 oils, niacinates and the like), bone anti-resorptives (bisphosponates, estrogens, selective estrogen receptor modulators (SERMs), calcitonin, and the like), bone anabolic agents (PTH and fragments e.g teriparatide, PTHRP and analogues e.g. BaO58), anti-diabetics (e.g. insulin sensitizers, glucose absorption and synthesis inhibitors (e.g.
  • the compounds of this invention may be co- formulated or co-administered wherein said co-administration does not require dosing at exactly the same time but rather indicates that the patient is undergoing treatment with one or more of the additional agents during the timeframe of treatment with the selective androgen modulators of this invention.
  • the additional drug(s) for combination treatment can be administered concomitantly, sequentially or separately from the compounds of this invention.
  • the compounds of this invention may be administered according to different dosage scheduling and the dosage may be adjusted as deemed necessary by the subject or preferably by the subject in consultation with a qualified practitioner of medicine. Dosing of the compounds of this invention can take place by multiple routes and consequently, the dosing schedule and amounts are dependent not only on the particular subject's weight, sex, age, therapy contemplated, etc but also by the route of the drug chosen.
  • the compounds of this invention may be dosed by the oral route in a once daily, twice daily, three times daily or more than three times per day depending on the particular needs of that subject, the formulation of the drug, etc.
  • the dosage will typically be from about 0.01 mg to 500 mg of drug per daily dosage, for example from about 0.1 mg to about 10 mg, such as from about 0.1 mg to about 3 mg, or from about 0.1 mg to about 250 mg of drug per daily dosage, or from about 1 mg to about 150 mg of drug per daily dosage, or from aobut 5 mg to about 100 mg of drug per daily dosage.
  • the amount of compound dosed per day can be administered every day, every other day, every 2 days, every 3 days, every 4 days, every 5 days, etc.
  • a 5 mg per day dose can be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, etc.
  • a compound of this invention is dosed once every seven days.
  • the compounds of this invention can also be dosed on a monthly basis meaning that administration is done once per month.
  • the compounds of this invention can be dosed on a weekly basis (once a week), every other week, every three weeks or every four weeks for a single day or multiple days.
  • the compounds of this invention can also be dosed on an as needed or "pro re nata" "prn" schedule, and "on demand”. In this type of dosing, the compouonds of this invention are administered in a therapeutically effective dose at some time prior to commencement of an activity wherein the therapeutic effect of the compounds of this invention is desirable.
  • Administration can be immediately prior to such an activity, including about 0 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, or about 10 hours prior to such an activity, depending on the formulation.
  • the compounds of this invention can be prepared by a variety of synthetic routes and techniques known to those of skill in the art.
  • the processes disclosed herein should not be construed as limiting the examples or scope of the invention in any way but rather are provided as just some of the representative ways that the compounds of this invention can be or were prepared.
  • protective groups are employed in the synthesis of the compounds of this invention and it should be appreciated that there are a diverse array of protective groups and strategies that can be employed in organic synthesis (T.W.Green and P.G.M.Wuts (2006) Greene's Protective Groups in Organic Synthesis, herein incorporated by reference in its entirety) and that where a protective group is referred to generically, any appropriate protective group should be considered.
  • leaving groups are employed in the synthesis of compounds of this invention. Where a specific leaving group is referred to, it should be appreciated that other leaving groups might also be used. Leaving groups typically include those groups that can stabilize an anion. In the case of nucleophilic aromatic substitutions, the leaving group may be an anion or a neutrally charged group.
  • the leaving group for nucleophilic aromatic substitution may be a group that is not typically considered to be a stabilized anion (e.g. fluoride or hydride). While not intending to be bound by theory or the examples, some typical nucleophilic leaving groups include halogens, sulfonates (O-mesylates, O-tosylates, etc), hydrides, quaternized amines, nitro, and the like. Additional discussion and examples can be found in leading textbooks on organic chemistry including, for example, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th Edition, which is herein incorporated in its entirety.
  • an androgen receptor binding assay was performed.
  • the compounds of this invention are shown to demonstrate affinity for the androgen receptor.
  • the assay was performed as specified by the manufacturer (Invitrogen, Madison, WI). Briefly, 1 ⁇ l of 1OmM compound was added to 500 ⁇ l of AR screening buffer in a 1.5ml eppendorf tube to make a 2x10 "5 M stock. 10-fold serial dilutions of the test compounds were prepared ranging in concentration from 10 "5 M to 10 "12 M. Each dilution was added in triplicate to a black 384-microtiter plate. The test compounds will be diluted 2-fold in the final reaction.
  • 2x AR-FluormoneTM complex was prepared with 2nM Flourmone AL GreenTM and 3OnM AR. 25 ⁇ l of 2x complex was aliquoted to each reaction well, such that the final reaction volume was 50 ⁇ l per well. Plate was sealed with a foil cover and incubated in the dark at room temperature for 4 h. Polarization values for each well were measured. The polarization values were plotted against the concentration of the test compound. The concentration of the test compound that results in half-maximum shift equals the IC 50 of the test compound. As a control, a competition curve for Rl 881 ( methyltrienolone) was performed for each assay. Curve Fitting was performed using GraphPad Prism® software from GraphPadTM Software Inc.
  • Binding data are reported as a single determination if the experiment was run once only and as the average of experiments if the binding experiment was performed two or more times with that compound. Results are set forth in Table 1.
  • this assay looks primarily at the ability of the selective androgens of this invention to increase muscle size in an immature, castrated rat.
  • androgenic effects are looked at primarily by weighing the prostate and seminal vesicles. Selective compounds will show a greater increase in the levator ani relative to the prostate and seminal vesicles when compared to testosterone treated, castrated animals or to intact animals that have not been treated. Immature Sprague Dawley male rats were obtained Charles River Laboratories (Stoneridge, NY).
  • GDX anesthetized and orchidectomized
  • SHAM sham surgery
  • Testosterone propionate (TP 1 mg/kg in 5% DMSO/95% corn oil) was administered by once daily subcutaneous injections, while the tested compounds of the invention were dosed in vehicle (typically 20% cyclodextrin or 0.5% carboxymethylcellulose) and administered by once daily oral gavage. The rats were then dosed once daily for 4 days. All animals were euthanized via carbon dioxide inhalation 24 hs after the last dose. The prostate, seminal vesicle and levator ani and bulba cavernous (LABC) tissues were removed, weighed and recorded. Body weights were recorded for each animal at baseline and at sacrifice. Results are set forth in Table 2. IN VIVO MODELS OF BONE LOSS AND PREVENTION
  • Compounds of this invention may also be assayed in vivo to determine their effect on preventing bone loss in animal models of bone loss.
  • Animal models of bone loss are well-known to those of ordinary skill in the art.
  • bone loss models include the rat and mouse ovariectomized models. Examples of such models are replete in the art, some non-limiting methods and examples are provided in Cesnjaj, et al European Journal of Clinical Chemistry and Clinical Biochemistry (1991), 29(4), 211-219; Y.L.
  • COMPOUND CHARACTERIZATION All solvents were commercially available and used without further purification. Reactions were monitored by thin-layer chromatography (TLC) on silica gel plates (60 F254; EMD Chemicals) which were visualized using ultraviolet light, iodine vapor, or vanillin stain. Flash chromatography was performed on silica gel (230-400 mesh, Silicycle) using commercially available high purity solvents. 1 H and 13 C NMR spectra were determined in CDCI 3 , MeOH- ⁇ , DMSO-t/g, or acetone- d(, using either a Varian Unity 400 MHz spectrometer or a Varian Unity 500 MHz spectrometer.
  • N'-((2i?, 35)-2-(4-chloro-5-cyano-lH-indol-l-yl)-3- hydroxybutanoyl)-4-cyanobenzohydrazide (0.51 g, 1.21 mmol) in DMF (15 mL) were added imidazole (329 mg, 4.83 mmol) and TBSCl (365 mg, 2.42 mmol) at 0 0 C. After addition, the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by adding ice-water and extracted with EtOAc. The EtOAc extracts were washed with water, brine and dried over Na 2 SO 4 .
  • Example 3 4-chloro- 1 -(( 1 R, 2S)- 1 -(5 -(4-cyanophenyl)- 1 ,3 ,4-oxadiazol-2-yl)-2- hydroxypropyl)indoline-5-carbonitrile
  • the binding data shown in table 1 is from the result of a single or multiple determinations based on the same compound. Where multiple data points have been taken, the value reported is the average of the multiple determinations.
  • Prostate, seminal vesicle and levator ani bulbus cavernosus are all represented as % relative to sham. After sacrifice, organ weights of young, orchidectomized rats treated with compound for 4 days are compared to sham operated animals. Preferred compounds of this invention demonstrate increased levator ani stimulation relative to prostate and/or seminal vesicles

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Abstract

Cette invention porte sur des composés de formule I, Ia, Ib ou Ic ou sur des sels de ceux-ci, sur des compositions pharmaceutiques comprenant un composé de formule I, Ia, Ib ou Ic, et un excipient pharmaceutiquement acceptable, sur des procédés de modulation du récepteur aux androgènes, des procédés de traitement de maladies traitées avantageusement par un modulateur du récepteur aux androgènes (par exemple, une sarcopénie, un cancer de la prostate, une contraception, des troubles ou maladies liés à un diabète de type 2, une anémie, une dépression et une maladie rénale) et des procédés de fabrication des composés de formule I et d'intermédiaires utiles dans leur préparation.
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