US2010234422A1PendingUtilityA1
Sulfonylated Heterocycles Useful for Modulation of the Progesterone Receptor
Est. expiryMar 6, 2027(~0.6 yrs left)· nominal 20-yr term from priority
A61P 3/04A61P 35/00A61P 43/00A61P 5/24A61P 25/22A61P 25/00C07D 401/04C07D 403/04A61P 15/02A61P 15/08A61P 15/00A61P 1/00A61P 15/18
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Claims
Abstract
Compounds of the following structure are provided, wherein n, R 1 -R 3 and R 6 -R 9 are defined below, as are methods of preparing and using these compounds for contraception; treating or preventing fibroids, uterine leiomyomata, endometriosis, dysfunctional bleeding, polycystic ovary syndrome, and hormone-dependent carcinomas; providing hormone replacement therapy; stimulating food intake; synchronizing estrus; and treating cycle-related symptoms.
Claims
exact text as granted — not AI-modified1 . A compound of the structure:
wherein:
n is 2 or 3;
Z is CR 4 R 5 , NR 4 , or O;
R 1 is selected from the group consisting of C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 1 to C 6 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, C 3 to C 6 alkenyl, substituted C 3 to C 6 alkenyl, C 3 to C 6 alkynyl, and substituted C 3 to C 6 alkynyl;
R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of H, halogen, CN, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, —(CH m X r ) z CH p X q , C 3 to C 6 cycloalkyl, O—C 1 to C 6 alkyl, substituted O—C 1 to C 6 alkyl, O—(CH m X r ) z CH p X q , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; or
R 2 and R 4 ; or R 2 and R 5 ; or R 3 and R 4 ; or R 3 and R 5 are joined to form a carbocyclic or heterocyclic ring containing from 3 to 8 atoms;
R 6 , R 7 and R 8 are independently selected from the group consisting of H, halogen, CN, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, —(CH m X r ) z CH p X q , C 3 to C 6 cycloalkyl, O—C 1 to C 6 alkyl, substituted O—C 1 to C 6 alkyl, O—(CH m X r ) z CH p X q , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle;
X is halogen;
m and r are, independently, 0 to 2, provided that m+r=2;
p and q are, independently, 0 to 3, provided that p+q=3;
z is 0 to 10; and
R 9 is selected from the group consisting of H, C 1 to C 6 alkyl, C(O)O—C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, and substituted C 3 to C 6 cycloalkyl;
or a pharmaceutically acceptable salt, prodrug, tautomer, or metabolite thereof.
2 . The compound according to claim 1 , wherein R 1 is C 1 to C 6 alkyl.
3 . The compound according to claim 1 , wherein R 2 , R 3 , R 6 , or R 8 is H.
4 . The compound according to claim 1 , wherein n is 2.
5 . The compound according to claim 1 , wherein Z is CR 4 R 5 .
6 . The compound according to claim 1 , wherein R 4 or R 5 is H or C 1 to C 6 alkyl.
7 . The compound according to claim 1 , wherein R 7 is H or halogen.
8 . The compound according to claim 1 , wherein R 9 is C 1 to C 6 alkyl.
9 . The compound according to claim 1 , wherein:
R 1 is C 1 to C 6 alkyl; R 2 , R 3 , R 6 , and R 8 are H; R 4 and R 5 are, independently, H or C 1 to C 6 alkyl; R 7 is H or halogen; and R 9 is C 1 to C 6 alkyl.
10 . The compound according to claim 1 , selected from the group consisting of 1-methyl-5-[1-(methylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrrole-2-carbonitrile; 5-[1-(ethylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl]-1-methyl-1H-pyrrole-2-carbonitrile; and 1-methyl-5-[1-(propylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrrole-2-carbonitrile; or a pharmaceutically acceptable salt, prodrug, tautomer, or metabolite thereof.
11 . A method of contraception, treating or preventing fibroids, uterine leiomyomata, endometriosis, dysfunctional bleeding, polycystic ovary syndrome, or hormone-dependent carcinomas, providing hormone replacement therapy, stimulating food intake, synchronizing estrus, or treating cycle-related symptoms, said method comprising administering to a mammal in need thereof a compound of claim 1 .
12 . A method for preparing a compound of formula I:
wherein:
n is 2 or 3;
Z is CR 4 R 5 , NR 4 , or O;
R 1 is selected from the group consisting of C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 1 to C 6 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, C 3 to C 6 alkenyl, substituted C 3 to C 6 alkenyl, C 3 to C 6 alkynyl, and substituted C 3 to C 6 alkynyl;
R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of H, halogen, CN, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, —(CH m X r ) z CH p X q , C 3 to C 6 cycloalkyl, O—C 1 to C 6 alkyl, substituted O—C 1 to C 6 alkyl, O—(CH m X r ) z CH p X q , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; or
R 2 and R 4 ; or R 2 and R 5 ; or R 3 and R 4 ; or R 3 and R 5 are joined to form a carbocyclic or heterocyclic ring containing from 3 to 8 atoms;
R 6 , R 7 and R 8 are independently selected from the group consisting of H, halogen, CN, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, —(CH m X r ) z CH p X q , C 3 to C 6 cycloalkyl, O—C 1 to C 6 alkyl, substituted O—C 1 to C 6 alkyl, O—(CH m X r ) z CH p X q , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle;
X is halogen;
m and r are, independently, 0 to 2, provided that m+r=2;
p and q are, independently, 0 to 3, provided that p+q=3;
z is 0 to 10; and
R 9 is selected from the group consisting of H, C 1 to C 6 alkyl, C(O)O—C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, and substituted C 3 to C 6 cycloalkyl;
or a pharmaceutically acceptable salt, prodrug, tautomer, or metabolite thereof;
said method comprising:
(a) reacting a cyanopyrrole boronic acid or a tin derivative thereof and a substituted heterocycle of the structure:
wherein, LG is a leaving group;
(b) sulfonylating the product of step (a).
13 . The method according to claim 12 , wherein the product of step (a) is of the structure:
14 . The method according to claim 12 , wherein said boronic acid is of the structure:
15 . A method for preparing a compound of the structure:
wherein:
n is 2 or 3;
Z is CR 4 R 5 , NR 4 , or O;
R 1 is selected from the group consisting of C 1 to C 6 alkyl, C 3 to C 5 cycloalkyl, substituted C 1 to C 6 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, C 3 to C 6 alkenyl, substituted C 3 to C 6 alkenyl, C 3 to C 6 alkynyl, and substituted C 3 to C 6 alkynyl;
R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of H, halogen, CN, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, —(CH m X r ) z CH p X q , C 3 to C 6 cycloalkyl, O—C 1 to C 6 alkyl, substituted O—C 1 to C 6 alkyl, O—(CH m X r ) z CH p X q , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; or
R 2 and R 4 ; or R 2 and R 5 ; or R 3 and R 4 ; or R 3 and R 5 are joined to form a carbocyclic or heterocyclic ring containing from 3 to 8 atoms;
R 6 , R 7 and R 8 are independently selected from the group consisting of H, halogen, CN, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, —(CH m X r ) z CH p X q , C 3 to C 6 cycloalkyl, O—C 1 to C 6 alkyl, substituted O—C 1 to C 6 alkyl, O—(CH m X r ) z CH p X q , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle;
X is halogen;
m and r are, independently, 0 to 2, provided that m+r=2;
p and q are, independently, 0 to 3, provided that p+q=3;
z is 0 to 10; and
R 9 is selected from the group consisting of H, C 1 to C 6 alkyl, C(O)O—C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, and substituted C 3 to C 6 cycloalkyl;
or a pharmaceutically acceptable salt, prodrug, tautomer, or metabolite thereof;
said method comprising:
(a) sulfonylating a compound of the structure:
(b) coupling the product of step (a) with a cyanopyrrole boronic acid or a tin derivative thereof.
16 . The method according to claim 15 , wherein the product of step (a) is of the structure:
17 . A method for preparing a compound of the structure:
wherein:
n is 2 or 3;
Z is CR 4 R 5 , NR 4 , or O;
R 1 is selected from the group consisting of C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 1 to C 6 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, C 3 to C 6 alkenyl, substituted C 3 to C 6 alkenyl, C 3 to C 6 alkynyl, and substituted C 3 to C 6 alkynyl;
R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of H, halogen, CN, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, —(CH m X r ) z CH p X q , C 3 to C 6 cycloalkyl, O—C 1 to C 6 alkyl, substituted O—C 1 to C 6 alkyl, O—(CH m X r ) z CH p X q , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; or
R 2 and R 4 ; or R 2 and R 5 ; or R 3 and R 4 ; or R 3 and R 5 are joined to form a carbocyclic or heterocyclic ring containing from 3 to 8 atoms;
R 6 , R 7 and R 8 are independently selected from the group consisting of H, halogen, CN, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, —(CH m X r ) z CH p X q , C 3 to C 6 cycloalkyl, O—C 1 to C 6 alkyl, substituted O—C 1 to C 6 alkyl, O—(CH m X r ) z CH p X q , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle;
X is halogen;
m and r are, independently, 0 to 2, provided that m+r=2;
p and q are, independently, 0 to 3, provided that p+q=3;
z is 0 to 10; and
R 9 is selected from the group consisting of H, C 1 to C 6 alkyl, C(O)O—C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, and substituted C 3 to C 6 cycloalkyl;
or a pharmaceutically acceptable salt, prodrug, tautomer, or metabolite thereof;
said method comprising:
(a) sulfonylating a compound of the structure:
(b) brominating the product of step (a); and
(c) coupling the product of step (b) with a cyanopyrrole boronic acid or a tin derivative thereof.
18 . The method according to claim 17 , wherein the product of step (a) is of the structure:
19 . The method according to claim 17 , wherein the product of step (b) is of the structure and LG is bromine:Join the waitlist — get patent alerts
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