P13K Inhibitors for the Treatment of Endometriosis
This invention relates to a method of treating and/or preventing endometriosis comprising administering a PI3K inhibitor. The PI3K inhibitor can also be administered combined with a hormonal suppressor. The invention further relates to the treatment of endometriosis-related infertility.
1 . A method of treating and/or preventing endometriosis in an individual comprising administering a therapeutically effective amount of a PI3K inhibitor.
2 . The method according to claim 1 , wherein said PI3K inhibitor is administered in combination with a hormonal suppressor.
3 . The method according to claim 1 , wherein said hormonal suppressor is selected from the group consisting of a GnRH antagonist, GnRH agonist, aromatase inhibitor, progesterone receptor modulator and an estrogen receptor modulator.
4 . The method according to claim 1 , wherein said PI3K inhibitor is administered alone or in combination with drugs for the treatment of endometriosis-related infertility.
5 . The method according claim 1 , wherein said PI3K inhibitor is a compound according to Formula (I):
as well as its geometrical isomers, its optically active forms as enantiomers, diastereo-mers and its racemate forms, as well as pharmaceutically acceptable salts and pharma-ceutically active derivatives thereof, wherein
A is a 5-8 membered heterocyclic or carbocyclic group, wherein said carbocyclic group may be fused with aryl, heteroaryl, cycloalkyl or heterocycloalkyl;
X is S, O or NH;
Y 1 and Y 2 are each independently selected from the group consisting of S, O or —NH;
Z is either S or O; and
R 1 is selected from the group consisting of H, CN, carboxy, acyl, C 1 -C 6 -alkoxy, halogen, hydroxy, acyloxy, C 1 -C 6 -alkyl carboxy, C 1 -C 6 -alkyl acyloxy, C 1 -C 6 -alkyl alkoxy, alkoxycarbonyl, C 1 -C 6 -alkyl alkoxycarbonyl, aminocarbonyl, C 1 -C 6 -alkyl aminocarbonyl, acylamino, C 1 -C 6 -alkyl acylamino, ureido, C 1 -C 6 -alkyl ureido, amino, C 1 -C 6 -alkyl amino, ammonium, sulfonyloxy, C 1 -C 6 -alkyl sulfonyloxy, sulfonyl, C 1 -C 6 -alkyl sulfonyl, sulfinyl, C 1 -C 6 -alkyl sulfinyl, sulfanyl, C 1 -C 6 -alkyl sulfanyl, sulfonylamino, C 1 -C 6 -alkyl sulfonylamino and carbamate;
R 2 is selected from the group consisting of H, halogen, acyl, amino, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkyl carboxy, C 1 -C 6 -alkyl acyl, C 1 -C 6 -alkyl alkoxycarbonyl, C 1 -C 6 -alkyl aminocarbonyl, C 1 -C 6 -alkyl acyloxy, C 1 -C 6 -alkyl acylamino, C 1 -C 6 -alkyl ureido, C 1 -C 6 -alkyl amino, C 1 -C 6 -alkyl alkoxy, C 1 -C 6 -alkyl sulfanyl, C 1 -C 6 -alkyl sulfinyl, C 1 -C 6 -alkyl sulfonyl, C 1 -C 6 -alkyl sulfonylaminoaryl, aryl, C 3 -C 8 -cycloalkyl or heterocycloalkyl, C 1 -C 6 -alkyl aryl, C 2 -C 6 -alkenyl-aryl, C 2 -C 6 -alkynyl aryl, carboxy, cyano, hydroxy, C 1 -C 6 -alkoxy, nitro, acylamino, ureido, C 1 -C 6 -alkyl carbamate, sulfonylamino, sulfanyl and sulfonyl;
n is 0, 1 or 2;
6 . The method according to claim 5 , wherein Y 1 and Y 2 are both O.
7 . The method according to claim 5 , wherein n is either 1 or 2; and R 1 and R 2 are both H.
8 . The method according to claim 5 , wherein X is S; Y 1 and Y 2 are both O; R 1 and R 2 are as above-defined and n is 0.
9 . The method according to claim 1 , wherein said PI3K inhibitor is a compound according to Formula (I′):
as well as its geometrical isomers, its optically active forms as enantiomers, diastereo-mers and its racemate forms, as well as pharmaceutically acceptable salts and pharmaceutically active derivatives thereof, wherein R 1 , Y 1 are as defined in above, and W is selected from O, S, —NR 3 wherein R 3 is H or an unsubstituted or substituted C 1 -C 6 alkyl group.
10 . The method according to claim 1 , wherein said PI3K inhibitor is a compound according to Formula (II):
as well as its geometrical isomers, its optically active forms as enantiomers, diastereo-mers and its racemate forms, as well as pharmaceutically acceptable salts and pharma-ceutically active derivatives thereof, wherein
A is selected from the group consisting of dioxol, dioxin, dihydrofuran, (dihydro) furanyl, (dihydro)oxazinyl, pyridinyl, isooxazolyl, oxazolyl (dihydro)napthalenyl, pyrimidinyl, triazolyl, imidazolyl, pyrazinyl, thiazolidinyl, thiadiazolyl and oxadiazolyl;
R 2 is selected from the group consisting of H, halogen, acyl, amino, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkyl carboxy, C 1 -C 6 -alkyl acyl, C 1 -C 6 -alkyl alkoxycarbonyl, C 1 -C 6 -alkyl aminocarbonyl, C 1 -C 6 -alkyl acyloxy, C 1 -C 6 -alkyl acylamino, C 1 -C 6 -alkyl ureido, C 1 -C 6 -alkyl carbamate, C 1 -C 6 -alkyl amino, C 1 -C 6 -alkyl alkoxy, C 1 -C 6 -alkyl sulfanyl, C 1 -C 6 -alkyl sulfinyl, C 1 -C 6 -alkyl sulfonyl, C 1 -C 6 -alkyl sulfonylaminoaryl, aryl, C 3 -C 8 -cycloalkyl or heterocycloalkyl, C 1 -C 6 -alkyl aryl, C 2 -C 6 -alkenyl-aryl, C 2 -C 6 -alkynyl aryl, carboxy, cyano, hydroxy, C 1 -C 6 -alkoxy, nitro, acylamino, ureido, sulfonylamino, sulfanyl and sulfonyl.
11 . The method according to claim 1 , wherein said PI3K inhibitor is a compound according to Formula (II′):
as well as its geometrical isomers, its optically active forms as enantiomers, diastereo-mers and its racemate forms, as well as pharmaceutically acceptable salts and pharma-ceutically active derivatives thereof, wherein:
Z, Y 1 , R 1 , R 2 are as above defined, n is 0 or 1.
12 . The method according to claim 11 , wherein Y 1 is O.
13 . The method according to claim 11 , wherein R 1 is selected in the group consisting of C 1 -C 6 -alkyl, C 1 -C 6 -alkyl aryl, aryl, C 3 -C 8 -cycloalkyl, heterocycloalkyl, C 1 -C 6 -alkyl aryl, C 2 -C 6 -alkenyl aryl and C 2 -C 6 -alkynyl aryl.
14 . The method according to claim 1 , wherein said PI3K inhibitor is a compound according to Formula (III):
as well as its geometrical isomers, its optically active forms as enantiomers, diastereo-mers and its racemate forms, as well as pharmaceutically acceptable salts and pharmaceutically active derivatives thereof, wherein
R 1 and R 2 are as above defined.
15 . The method according to claim 1 , wherein said PI3K inhibitor is a compound according to any one of Formulae (IV), (V) and (VI):
16 . The method according to claim 15 , wherein said PI3K inhibitor is 5-Quinoxalin-6-ylmethylene-thiazolidine-2,4-dione.
17 . The method according to claim 1 , wherein said PI3K inhibitor is a compound according to Formula (VII):
as well as its geometrical isomers, its optically active forms as enantiomers, diastereo-mers and its racemate forms, as well as pharmaceutically acceptable salts and pharmaceutically active derivatives thereof, wherein
A is an 5-8 membered heterocyclic group or an carbocyclic group which may be fused with an aryl, an heteroaryl, an cycloalkyl or an heterocycloalkyl;
X is S, O or —NR 3 ;
Y is either S or O;
R 1 is selected from the group consisting of H, CN, carboxy, acyl, C 1 -C 6 -alkoxy, halogen, hydroxy, acyloxy, C 1 -C 6 -alkyl carboxy, C 1 -C 6 -alkyl acyloxy, C 1 -C 6 -alkyl alkoxy, alkoxycarbonyl, C 1 -C 6 -alkyl alkoxycarbonyl, aminocarbonyl, C 1 -C 6 -alkyl aminocarbonyl, acylamino, C 1 -C 6 -alkyl acylamino, ureido, C 1 -C 6 -alkyl ureido, amino, C 1 -C 6 -alkyl amino, ammonium, sulfonyloxy, C 1 -C 6 -alkyl sulfonyloxy, sulfonyl, C 1 -C 6 -alkyl sulfonyl, sulfinyl, C 1 -C 6 -alkyl sulfinyl, sulfanyl, C 1 -C 6 -alkyl sulfanyl, sulfonylamino, C 1 -C 6 -alkyl sulfonylamino and carbamate;
R 2 is selected from the group consisting of H, halogen, acyl, amino, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkyl carboxy, C 1 -C 6 -alkyl acyl, C 1 -C 6 -alkyl alkoxycarbonyl, C 1 -C 6 -alkyl aminocarbonyl, C 1 -C 6 -alkyl acyloxy, C 1 -C 6 -alkyl acylamino, C 1 -C 6 -alkyl ureido, C 1 -C 6 -alkyl carbamate, C 1 -C 6 -alkyl amino, C 1 -C 6 -alkyl alkoxy, C 1 -C 6 -alkyl sulfanyl, C 1 -C 6 -alkyl sulfinyl, C 1 -C 6 -alkyl sulfonyl, C 1 -C 6 -alkyl sulfonylaminoaryl, aryl, heteroaryl, C 3 -C 8 -cycloalkyl or heterocycloalkyl, C 1 -C 6 -alkyl aryl, C 1 -C 6 -alkyl heteroaryl, C 2 -C 6 -alkenyl-aryl or -heteroaryl, C 2 -C 6 -alkynyl aryl or -heteroaryl, carboxy, cyano, hydroxy, C 1 -C 6 -alkoxy, nitro, acylamino, ureido, sulfonylamino, sulfanyl and sulfonyl;
G is selected from the group consisting of C 1 -C 6 -alkoxy, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkyl aryl, cyano and a sulfonyl moiety; and
R 3 is either H or C 1 -C 6 -alkyl.
18 . The method according claim 17 , wherein A is selected from the group consisting of 2H-(benzo-1,3-dioxolanyl), 2H, 3H-benzo-1,4-dioxanyl, 2,3-dihydrobenzofuranyl, anthraquinonyl, 2,2-difluorobenzo-1,3-dioxolenyl, 1,3-dihydrobenzofuranyl, benzofuranyl, 4-methyl-2H-benzo-1,4-oxazin-3-onyl, pyridinyl, pyrazinyl, 4-methyl-2H and 3H-benzo-1,4-oxazinyl.
19 . The method according to claim 17 , wherein A is either a dioxolenyl or a pyridinyl moiety.
20 . The method according to claim 17 , wherein R 1 and/or R 2 are H.
21 . The method according to claim 17 , wherein G is selected from the group consisting of C 1 -C 6 -alkoxy, cyano or a sulfonyl moiety.
22 . The method according to claim 17 , G is a sulfonyl moiety of the formula —SO 2 —R 4 , whereby R 4 is selected from the group consisting of H, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkyl carboxy, C 1 -C 6 -alkyl acyl, C 1 -C 6 -alkyl alkoxycarbonyl, C 1 -C 6 -alkyl aminocarbonyl, C 1 -C 6 -alkyl acyloxy, C 1 -C 6 -alkyl acylamino, C 1 -C 6 -alkyl ureido, C 1 -C 6 -alkyl carbamate, C 1 -C 6 -alkyl amino, C 1 -C 6 -alkyl alkoxy, C 1 -C 6 -alkyl sulfanyl, C 1 -C 6 -alkyl sulfinyl, C 1 -C 6 -alkyl sulfonyl, C 1 -C 6 -alkyl sulfonylaminoaryl, aryl, heteroaryl, C 3 -C 8 -cycloalkyl or heterocycloalkyl, C 1 -C 6 -alkyl aryl, C 1 -C 6 -alkyl heteroaryl, C 2 -C 6 -alkenyl-aryl or -heteroaryl, C 2 -C 6 -alkynyl aryl or -heteroaryl, carboxy, hydroxy, C 1 -C 6 -alkoxy, acylamino and sulfonylamino.
23 . The method according to claim 22 , wherein R 4 is selected from the group consisting of aryl, heteroaryl and C 1 -C 6 alkyl.
24 . The method according to claim 17 , wherein X is S; Y is O; R 1 and R 2 are H, and A is either a dioxolenyl or pyridinyl moiety.
25 . A pharmaceutical composition comprising the PI3K inhibitor of the Formula (I) of claim 5 , a hormonal suppressor and a pharmaceutically acceptable excipient.
26 . The pharmaceutical composition according to claim 25 , wherein said hormonal suppressor is selected from the group consisting of a GnRH antagonist, GnRH agonist, aromatase inhibitor, progesterone receptor modulator and an estrogen receptor modulator.
27 . (canceled)
28 . The pharmaceutical composition according to claim 25 , wherein said PI3K inhibitor is 5-Quinoxalin-6-ylmethylene-thiazolidine-2,4-dione.