US 6,645,974 B2 · Androgen receptor modulators and methods for use thereof

Abstract

Compounds of structural formula (I) as herein defined are disclosed as useful in a method for modulating the androgen receptor in a tissue selective manner in a patient in need of such modulation, as well as in a method of agonizing the androgen receptor in a patient, and in particular the method wherein the androgen receptor is antagonized in the prostate of a male patient or in the uterus of a female patient and agonized in bone and/or muscle tissue. These compounds are useful in the treatment of conditions caused by androgen deficiency or which can be ameliorated by androgen administration, including: osteoporosis, periodontal disease, bone fracture, bone damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, post-menopausal symptoms in women, atherosclerosis, hypercholesterolemia, hyperlipidemia, aplastic anemia and other hematopoietic disorders, pancreatic cancer, renal cancer, arthritis and joint repair, alone or in combination with other active agents. In addition, these compounds are useful as pharmaceutical composition ingredients alone and in combination with other active agents.

A method for modulating the androgen receptor in a tissue selective manner in a patient in need of such modulation, comprising administering a therapeutically effective amount of a compound of structural formula I:

wherein:
“a” and “b” are independently selected from a single bond and a double bond;
R1 is selected from:
(1) C1-3 alkyl,
(2) C2-3 alkenyl,
(3) C3-6 cycloalkyl,
(4) C1-3 alkyl wherein one or more of the hydrogen atoms has been replaced with a fluorine atom,
(5) aryl, and
(6) aryl-C1-3 alkyl;
R2 is selected from:
(1) aryl, either unsubstituted or substituted with one to three substituents selected from:
(a) halogen,
(b) aryl,
(c) C1-8 alkyl,
(d) C3-8 cycloalkyl,
(e) C3-8 cycloheteroalkyl,
(f) aryl C1-6alkyl,
(g) amino C0-6alkyl,
(h) C1-6alkylamino C0-6alkyl,
(i) (C1-6alkyl)2amino C0-6alkyl,
(j) aryl C0-6 alkylamino C0-6alkyl,
(k) (aryl C0-6 alkyl)2amino C0-6alkyl,
(l) C1-6 alkylthio,
(m) aryl C0-6alkylthio,
(n) C1-6 alkylsulfinyl,
(o) aryl C0-6alkylsulfinyl,
(p) C1-6 alkylsulfonyl,
(q) aryl C0-6alkylsulfonyl,
(r) C1-6 alkoxy C0-6alkyl,
(s) aryl C0-6 alkoxy C0-6alkyl,
(t) hydroxycarbonyl C0-6alkyl,
(u) C1-6 alkoxycarbonyl C0-6alkyl,
(v) aryl C0-6 alkoxycarbonyl C0-6alkyl,
(w) hydroxycarbonyl C1-6 alkyloxy,
(x) hydroxy C0-6alkyl,
(y) cyano,
(z) nitro,
(aa) perfluoroC1-4alkyl,
(bb) perfluoroC1-4alkoxy,
(cc) oxo,
(dd) C1-6 alkylcarbonyloxy,
(ee) aryl C0-6alkylcarbonyloxy,
(ff) alkyl C1-6 carbonylamino,
(gg) aryl C0-6 alkylcarbonylamino,
(hh) C1-6 alkylsulfonylamino,
(ii) aryl C0-6alkylsulfonylamino,
(jj) C1-6 alkoxycarbonylamino,
(kk) aryl C0-6 alkoxycarbonylamino,
(ll) C1-6alkylaminocarbonylamino,
(mm) aryl C0-6alkylaminocarbonylamino,
(nn) (C1-6alkyl)2 aminocarbonylamino,
(oo) (aryl C0-6alkyl)2 aminocarbonylamino,
(pp) (C1-6alkyl)2 aminocarbonyloxy,
(qq) (aryl C0-6alkyl)2 aminocarbonyloxy,
(rr) C0-6alkylcarbonyl C0-6alkyl, and
(ss) aryl C0-6alkylcarbonyl C0-6alkyl;
(2) C1-8 alkyl, unsubstituted or substituted with one to three substituents independently selected from:
(a) halogen,
(b) aryl,
(c) C1-8 alkyl,
(d) C3-8 cycloalkyl,
(e) C3-8 cycloheteroalkyl,
(f) amino,
(g) C1-6 alkylamino,
(h) (C1-6 alkyl)2amino,
(i) aryl C0-6 alkylamino,
(j) (aryl C0-6 alkyl)2amino,
(k) C1-6 alkylthio,
(l) aryl C0-6alkylthio,
(m) C1-6 alkylsulfinyl,
(n) aryl C0-6alkylsulfinyl,
(o) C1-6 alkylsulfonyl,
(p) aryl C0-6alkylsulfonyl,
(q) C1-6 alkoxy,
(r) aryl C0-6 alkoxy,
(s) hydroxycarbonyl,
(t) C1-6 alkoxycarbonyl,
(u) aryl C0-6 alkoxycarbonyl,
(v) hydroxycarbonyl C1-6 alkyloxy,
(w) hydroxy,
(x) cyano,
(y) nitro,
(z) perfluoroC1-4alkyl,
(aa) perfluoroC1-4alkoxy,
(bb) oxo,
(cc) C1-6 alkylcarbonyloxy,
(dd) aryl C0-6alkylcarbonyloxy,
(ee) alkyl C1-6 carbonylamino,
(if) aryl C0-6 alkylcarbonylamino,
(gg) C1-6 alkylsulfonylamino,
(hh) aryl C0-6alkylsulfonylamino,
(ii) C1-6 alkoxycarbonylamino,
(jj) aryl C0-6 alkoxycarbonylamino,
(kk) C1-6alkylaminocarbonylamino,
(ll) aryl C0-6alkylaminocarbonylamino,
(mm) (C1-6alkyl)2 aminocarbonylamino,
(nn) (aryl C0-6alkyl)2 aminocarbonylamino,
(oo) (C1-6alkyl)2 aminocarbonyloxy,
(pp) (aryl C0-6alkyl)2 aminocarbonyloxy, and
(qq) spiro-C3-8cycloalkyl;
(3) perfluoroC1-8 alkyl,
(4) C2-8 alkenyl, unsubstituted or substituted with one to three substituents independently selected from:
(a) halogen,
(b) aryl,
(c) C1-8 alkyl,
(d) C3-8 cycloalkyl,
(e) C3-8 cycloheteroalkyl,
(f) amino,
(g) C1-6 alkylamino,
(h) (C1-6 alkyl)2amino,
(i) aryl C0-6 alkylamino,
(j) (aryl C0-6 alkyl)2amino,
(k) C1-6 alkylthio,
(l) aryl C0-6alkylthio,
(in) C1-6 alkylsulfinyl,
(n) aryl C0-6alkylsulfinyl,
(o) C1-6 alkylsulfonyl,
(p) aryl C0-6alkylsulfonyl,
(q) C1-6 alkoxy,
(r) aryl C0-6 alkoxy,
(s) hydroxycarbonyl,
(t) C1-6 alkoxycarbonyl,
(u) aryl C0-6 alkoxycarbonyl,
(v) hydroxycarbonyl C1-6 alkyloxy,
(w) hydroxy,
(x) cyano,
(y) nitro,
(z) perfluoroC1-4alkyl,
(aa) perfluoroC1-4alkoxy,
(bb) oxo,
(cc) C1-6 alkylcarbonyloxy,
(dd) aryl C0-6alkylcarbonyloxy,
(ee) alkyl C1-6 carbonylamino,
(ff) aryl C0-6 alkylcarbonylamino,
(gg) C1-6 alkylsulfonylamino,
(hh) aryl C0-6alkylsulfonylamino,
(ii) C1-6 alkoxycarbonylamino,
(jj) aryl C0-6 alkoxycarbonylamino,
(kk) C1-6alkylaminocarbonylamino,
(ll) aryl C0-6alkylaminocarbonylamino,
(mm) (C1-6alkyl)2 aminocarbonylamino,
(nn) (aryl C0-6alkyl)2 aminocarbonylamino,
(oo) (C1-6alkyl)2 aminocarbonyloxy,
(pp) (aryl C0-6alkyl)2 aminocarbonyloxy, and
(qq) spiro-C3-8cycloalkyl;
(5) C3-8 cycloalkyl, either unsubstituted or substituted with one to 3 substituents selected from:
(a) halogen,
(b) aryl,
(c) C1-8 alkyl,
(d) C3-8 cycloalkyl,
(e) C3-8 cycloheteroalkyl,
(f) aryl C1-6alkyl,
(g) amino C0-6alkyl,
(h) C1-6 alkylamino C0-6alkyl,
(i) (C1-6 alkyl)2amino C0-6alkyl,
(j) aryl C0-6 alkylamino C0-6alkyl,
(k) (aryl C0-6 alkyl)2amino C0-6alkyl,
(l) C1-6 alkylthio,
(m) aryl C0-6alkylthio,
(n) C1-6 alkylsulfinyl,
(o) aryl C0-6alkylsulfinyl,
(p) C1-6 alkylsulfonyl,
(q) aryl C0-6alkylsulfonyl,
(r) C1-6 alkoxy C0-6alkyl,
(s) aryl C0-6 alkoxy C0-6alkyl,
(t) hydroxycarbonyl C0-6alkyl,
(u) C1-6 alkoxycarbonyl C0-6alkyl,
(v) aryl C0-6 alkoxycarbonyl C0-6alkyl,
(w) hydroxycarbonyl C1-6 alkyloxy,
(x) hydroxy C0-6alkyl,
(y) cyano,
(z) nitro,
(aa) perfluoroC1-4alkyl,
(bb) perfluoroC1-4alkoxy,
(cc) oxo,
(dd) C1-6 alkylcarbonyloxy,
(ee) aryl C0-6alkylcarbonyloxy,
(ff) alkyl C1-6 carbonylamino,
(gg) aryl C0-6 alkylcarbonylamino,
(hh) C1-6 alkylsulfonylamino,
(ii) aryl C0-6alkylsulfonylamino,
(jj) C1-6 alkoxycarbonylamino,
(kk) aryl C0-6 alkoxycarbonylamino,
(ll) C1-6alkylaminocarbonylamino,
(mm) aryl C0-6alkylaminocarbonylamino,
(nn) (C1-6alkyl)2 aminocarbonylamino,
(oo) (aryl C0-6alkyl)2 aminocarbonylamino,
(pp) (C1-6alkyl)2 aminocarbonyloxy,
(qq) (aryl C0-6alkyl)2 aminocarbonyloxy,
(rr) C0-6alkylcarbonyl C0-6alkyl, and
(ss) spiro-C3-8cycloalkyl;
(6) cycloheteroalkyl, unsubstituted or substituted with one to three substituents selected from:
(a) halogen,
(b) aryl,
(c) C1-8 alkyl,
(d) C3-8 cycloalkyl,
(e) C3-8 cycloheteroalkyl,
(f) aryl C1-6alkyl,
(g) amino C0-6alkyl,
(h) C1-6 alkylamino C0-6alkyl,
(i) (C1-6 alkyl)2amino C0-6alkyl,
(j) aryl C0-6 alkylamino C0-6alkyl,
(k) (aryl C0-6 alkyl)2amino C0-6alkyl,
(l) C1-6 alkylthio,
(m) aryl C0-6alkylthio,
(n) C1-6 alkylsulfinyl,
(o) aryl C0-6alkylsulfinyl,
(p) C1-6 alkylsulfonyl,
(q) aryl C0-6alkylsulfonyl,
(r) C1-6 alkoxy C0-6alkyl,
(s) aryl C0-6 alkoxy C0-6alkyl,
(t) hydroxycarbonyl C0-6alkyl,
(u) C1-6 alkoxycarbonyl C0-6alkyl,
(v) aryl C0-6 alkoxycarbonyl C0-6alkyl,
(w) hydroxycarbonyl C1-6 alkyloxy,
(x) hydroxy C0-6alkyl,
(y) cyano,
(z) nitro,
(aa) perfluoroC1-4alkyl,
(bb) perfluoroC1-4alkoxy,
(cc) oxo,
(dd) C1-6 alkylcarbonyloxy,
(ee) aryl C0-6alkylcarbonyloxy,
(ff) alkyl C1-6 carbonylamino,
(gg) aryl C0-6 alkylcarbonylamino,
(hh) C1-6 alkylsulfonylamino,
(ii) aryl C0-6alkylsulfonylamino,
(jj) C1-6 alkoxycarbonylamino,
(kk) aryl C0-6 alkoxycarbonylamino,
(ll) C1-6alkylaminocarbonylamino,
(mm) aryl C0-6alkylaminocarbonylamino,
(nn) (C1-6alkyl)2 aminocarbonylamino,
(oo) (aryl C0-6alkyl)2 aminocarbonylamino,
(pp) (C1-6alkyl)2 aminocarbonyloxy,
(qq) (aryl C0-6alkyl)2 aminocarbonyloxy, and
(rr) C0-6alkylcarbonyl C0-6alkyl, and
(ss) spiro C3-8cycloalkyl,
provided that any heteroatom substituent is bonded to a carbon atom in the cycloheteroalkyl ring;
R3 is selected from H and C1-8 alkyl, or R2 and R3, together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclic ring, optionally containing one or two additional heteroatoms selected from N, S, and O, optionally having one or more degrees of unsaturation, optionally fused to a 6-membered heteroaromatic or aromatic ring, either unsubstituted or substituted with one to three substituents selected from:
(1) halogen,
(2) aryl,
(3) C1-8 alkyl,
(4) C3-8 cycloalkyl,
(5) C3-8 cycloheteroalkyl,
(6) aryl C1-6alkyl,
(7) amino C0-6alkyl,
(8) C1-6 alkylamino C0-6alkyl,
(9) (C1-6 alkyl)2amino C0-6alkyl,
(10) aryl C0-6 alkylamino C0-6alkyl,
(11) (aryl C0-6 alkyl)2amino C0-6alkyl,
(12) C1-6 alkylthio,
(13) aryl C0-6alkylthio,
(14) C1-6 alkylsulfinyl,
(15) aryl C0-6alkylsulfinyl,
(16) C1-6 alkylsulfonyl,
(17) aryl C0-6alkylsulfonyl,
(18) C1-6 alkoxy C0-6alkyl,
(19) aryl C0-6 alkoxy C0-6alkyl,
(20) hydroxycarbonyl C0-6alkyl,
(21) C1-6 alkoxycarbonyl C0-6alkyl,
(22) aryl C0-6 alkoxycarbonyl C0-6alkyl,
(23) hydroxycarbonyl C0-6 alkyloxy,
(24) hydroxy C0-6alkyl,
(25) cyano,
(26) nitro,
(27) perfluoroC1-4alkyl,
(28) perfluoroC1-4alkoxy,
(29) oxo,
(30) C1-6 alkylcarbonyloxy,
(31) aryl C0-6alkylcarbonyloxy,
(32) C1-6 alkyl carbonylamino,
(33) aryl C0-6 alkylcarbonylamino,
(34) C1-6 alkylsulfonylamino,
(35) aryl C0-6alkylsulfonylamino,
(36) C1-6 alkoxycarbonylamino,
(37) aryl C0-6 alkoxycarbonylamino,
(38) C1-6alkylaminocarbonylamino,
(39) aryl C0-6alkylaminocarbonylamino,
(40) (C1-6alkyl)2 aminocarbonylamino,
(41) (aryl C0-6alkyl)2 aminocarbonylamino,
(42) (C1-6alkyl)2 aminocarbonyloxy,
(43) (aryl C0-6alkyl)2 aminocarbonyloxy, and
(44) spiro-C3-8cycloalkyl
provided that any heteroatom substituent is bonded to a carbon atom in the heterocyclic ring;
R4 and R5 are each independently selected from
(1) hydrogen,
(2) halogen,
(3) aryl,
(4) C1-8 alkyl,
(5) C3-8 cycloalkyl,
(6) C3-8 cycloheteroalkyl,
(7) aryl C1-6alkyl,
(8) amino C0-6alkyl,
(9) C1-6 alkylamino C0-6alkyl,
(10) (C1-6 alkyl)2amino C0-6alkyl,
(11) aryl C0-6 alkylamino C0-6alkyl,
(12) (aryl C0-6 alkyl)2amino C0-6alkyl,
(13) C1-6 alkylthio,
(14) aryl C0-6alkylthio,
(15) C1-6 alkylsulfinyl,
(16) aryl C0-6alkylsulfinyl,
(17) C1-6 alkylsulfonyl,
(18) aryl C0-6alkylsulfonyl,
(19) C1-6 alkoxy C0-6alkyl,
(20) aryl C0-6 alkoxy C0-6alkyl,
(21) hydroxycarbonyl C0-6alkyl,
(22) C1-6 alkoxycarbonyl C0-6alkyl,
(23) aryl C0-6 alkoxycarbonyl C0-6alkyl,
(24) hydroxycarbonyl C1-6 alkyloxy,
(25) hydroxy C0-6alkyl,
(26) cyano,
(27) nitro,
(28) perfluoroC1-4alkyl,
(29) perfluoroC1-4alkoxy,
(30) C0-6alkylcarbonyl C0-6alkyl,
(31) C1-6 alkylcarbonyloxy,
(32) aryl C0-6alkylcarbonyloxy,
(33) C1-6 alkyl carbonylamino,
(34) aryl C0-6 alkylcarbonylamino,
(35) C1-6 alkylsulfonylamino,
(36) aryl C0-6alkylsulfonylamino,
(37) C1-6 alkoxycarbonylamino,
(38) aryl C0-6 alkoxycarbonylamino,
(39) C1-6alkylaminocarbonylamino,
(40) aryl C0-6alkylaminocarbonylamino,
(41) (C1-6alkyl)2 aminocarbonylamino,
(42) (aryl C0-6alkyl)2 aminocarbonylamino,
(43) (C1-6alkyl)2 aminocarbonyloxy, and
(44) (aryl C0-6alkyl)2 aminocarbonyloxy;
or, R4 and R5 together form an oxo group or ═CH═R6 or a spiro C3-7 cycloalkyl ring, unsubstituted or substituted with R6;
R6 is selected from:
(1) hydrogen, and
(2) C1-4alkyl;
or a pharmaceutically acceptable salt thereof, and further wherein the tissue selective modulation of the androgen receptor is:
1) antagonizing in the prostate of a male patient or in the uterus of a female patient, and 2) agonizing in bone or muscle tissue.

332 more elements

Androgen receptor modulators and methods for use thereof

Life of this patent

Androgen receptor modulators and methods for use thereof

Life of this patent

Abstract

Claims25