	US 7,432,268 B2
	17β-hydroxysteroid dehydrogenase type 3 inhibitors for the treatment of androgen dependent diseases
Timothy Guzi, Chatham, N.J. (US); Kamil Paruch, Garwood, N.J. (US); Alan Mallams, Hackettstown, N.J. (US); Jocelyn D. Rivera, Monmouth Junction, N.J. (US); Ronald J. Doll, Convent Station, N.J. (US); Viyyoor M. Girijavallabhan, Parsippany, N.J. (US); Jonathan A. Pachter, Chatham, N.J. (US); Yi-Tsung Liu, Morris Township, N.J. (US); and Anil K. Saksena, Upper Montclair, N.J. (US)
Assigned to Schering Corporation, Kenilworth, N.J. (US)
Filed on Nov. 14, 2005, as Appl. No. 11/273,712.
Application 11/273712 is a division of application No. 11/045967, filed on Jan. 28, 2005, granted, now 7,138,396.
Application 11/045967 is a division of application No. 10/235627, filed on Sep. 05, 2002, granted, now 6,903,102.
Claims priority of provisional application 60/317715, filed on Sep. 06, 2001.
Prior Publication US 2006/0069103 A1, Mar. 30, 2006
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/497 (2006.01); A61K 31/445 (2006.01); A01N 43/40 (2006.01); C07D 241/02 (2006.01); C07D 211/70 (2006.01); C07D 211/82 (2006.01); C07D 213/06 (2006.01)

U.S. Cl. 514—252.11 [514/253.13; 514/316; 544/357; 544/365; 546/349]

16 Claims

1. A compound of the formula (I):

or a pharmaceutically acceptable salt of said compound or of said prodrug wherein,

R¹and R²are the same or different and are independently selected from the group consisting of aryl, heteroaryl, arylalkyl and heteroarylalkyl, each optionally substituted with one to six groups selected from the group consisting of:

a) halogen;

b) —OCF₃or —OCHF₂;

c) —CF₃;

d) —CN;

e) alkyl or R¹⁸-alkyl;

f) heteroalkyl or R¹⁸-heteroalkyl;

g) aryl or R¹⁸-aryl;

h) heteroaryl or R¹⁸-heteroaryl;

i) arylalkyl or R¹⁸-arylakyl;

j) heteroarylalkyl or R¹⁸-heteroarylalkyl;

k) hydroxy;

l) alkoxy;

m) aryloxy;

n) —SO₂-alkyl;

o) —NR¹¹R¹²;

p) —N(R¹¹)C(O)R¹³,

q) methylenedioxy;

r) difluoromethylenedioxy;

s) trifluoroalkoxy;

t) —SCH₃or —SCF₃; and

u) —SO₂CF₃or —NHSO₂CF₃;

R³is H, —OH, alkoxy or alkyl, provided that when X is N, R³is not —OH or alkoxy;

R⁴, R⁵, R⁷and R⁸are the same or different and are independently selected from the group consisting of H, OH, OR¹⁴, —NR¹¹R¹², —N(R¹¹)C(O)R¹³, alkyl, heteroalkyl, aryl, cycloalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,

provided that when Z and/or X is N, then R⁴, R⁵, R⁷and R⁸are not OH, OR¹⁴, —NR¹¹R¹², or —N(R¹¹)C(O)R¹³;

R⁶is selected from the group consisting of —C(O)R¹⁵and —SO₂R¹⁵;

R⁹and R¹⁰are the same or different and are independently selected from the group consisting of H, F, —CF₃, alkyl, cycloalkyl, arylalkyl, heteroalkyl, heteroarylalkyl, heterocycloalkyl, hydroxy, alkoxy, aryloxy, —NR¹¹R¹²and —N(R¹¹)C(O)R¹³, provided that when Z is N, then R⁹and R¹⁰are each not F, hydroxy, alkoxy, aryloxy, —NR¹¹R¹²or

—N(R¹¹)C(O)R¹³;

R¹¹is selected from the group consisting of H, alkyl, aryl and heteroaryl;

R¹²is selected from the group consisting of H, alkyl, aryl and heteroaryl;

R¹³is selected from the group consisting of alkyl, alkoxy and aryloxy;

R¹⁴is selected from the group consisting of H, alkyl, aryl and heteroaryl;

R¹⁵is selected from the group consisting of —NR¹⁶R¹⁷, —OR¹⁶, alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl and heteroarylalkyl, each optionally substituted with R¹⁸; R¹⁶and R¹⁷are the same or different and are independently selected from the group consisting of H, alkyl, aryl, arylalkyl, heteroalkyl and heteroaryl, each optionally substituted with R¹⁸, provided that when R¹⁵is —OR¹⁶, R¹⁶is not H;

R¹⁸is one to four substituents each independently selected from the group consisting of lower alkyl, halo, cyano, nitro, haloalkyl, hydroxy, alkoxy, alkoxy carbonyl, carboxy, carboxyalkyl, carboxamide, mercapto, amino, alkylamino, dialkylamino, sulfonyl, sulfonamido, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl and heteroaryl; and

either X=Z=N, or X=Z=C or X is C and Z is N,wherein the term “heteroaryl” refers to 5- or 10-membered single or benzofused aromatic ring consisting of 1 to 3 heteroatoms independently selected from the group consisting of —O—, —S, and —N═, provided that the rings do not possess adjacent oxygen and/or sulfur atoms, wherein said heteroaryl can be unsubstituted or substituted with one, two, or three substituents independently selected from lower alkyl, halo, cyano, nitro, haloalkyl, hydroxy, alkoxy, carboxy, carboxyalkyl, carboxamide, mercapto, amino, alkylamino and dialkylamino; the term “heteroarylalkyl” refers to a heteroaryl group bonded through an alkyl group; the term “heterocycloalkyl” refers to a non-aromatic, heterocyclic ring of 3-7 atoms containing 1-3 heteroatoms selected from N, O and S; and the term “heteroalkyl” refers to an alkyl group which containing at least one heteroatom.