Contraceptive agents

Patent metadata

Field	Value
Publication number	US-9670247-B2
Application number	US-201313932778-A
Country	US
Kind code	B2
Filing date	Jul 1, 2013
Priority date	Jul 2, 2012
Publication date	Jun 6, 2017
Grant date	Jun 6, 2017

Abstract

The invention provides compounds of formula I, II, III, or IV:

wherein R 1 to R 11 , X, and Y have any of the values defined in the specification. The compounds inhibit Na, K-ATPase α4 and are useful as contraceptive agents.

First claim

The invention claimed is:

1. A compound of formula:

wherein:
R 1 is H, (C 1 -C 6 )alkyl, or R c , wherein the (C 1 -C 6 )alkyl is optionally substituted with one or more halo or (C 1 -C 6 )alkoxy;
R 2 is H or (C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl is optionally substituted with one or more halo or (C 1 -C 6 )alkoxy;
R 3 is H or (C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl is optionally substituted with one or more halo or (C 1 -C 6 )alkoxy;
R 4 is R a , cyano, formyl, carboxy, hydroximinomethyl, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aryl, heteroaryl, or (C 1 -C 4 )alkanoyl, wherein the (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, and (C 1 -C 4 )alkanoyl is optionally substituted with one or more groups selected from hydroxy, halo, aryl, and heteroaryl; wherein any aryl and heteroaryl of R 4 is optionally substituted with one or more R b ;
R 5 is H or (C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl is optionally substituted with one or more halo or (C 1 -C 6 )alkoxy;
R 6 is H or (C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl is optionally substituted with one or more halo or (C 1 -C 6 )alkoxy; and
R 7 is H or (C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl is optionally substituted with one or more halo or (C 1 -C 6 )alkoxy; or R 6 and R 7 taken together form a (C 1 -C 6 )alkylene;
R a , is a 4, 5, or 6 membered saturated or partially unsaturated heterocyclic ring comprising at least one carbon atom and at least one heteroatom selected from S, or NH in the ring, which ring is optionally substituted with one or more oxo (═O);
R b , is aryl or aryl(C 1 -C 6 )alkyl, wherein the aryl or aryl(C 1 -C 6 )alkyl is optionally substituted with one or more (C 1 -C 6 )alkoxy or halo;
R c , is a C-linked amino acid, a C-linked dipeptide, —C(═O)CH 2 CH 2 COOH, —P(═O)(OH) 2 , or:

R d is H, (C 1 -C 6 )alkanoyl, or (C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkanoyl and the (C 1 -C 6 )alkyl are each optionally substituted with one or more halo or (C 1 -C 6 )alkoxy; and R e is H, (C 1 -C 6 )alkanoyl, or (C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkanoyl and the (C 1 -C 6 )alkyl are each optionally substituted with one or more halo or (C 1 -C 6 )alkoxy; or R d and R e taken together form a (C 1 -C 6 )alkylene; and
R f is H, (C 1 -C 6 )alkanoyl, or (C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkanoyl and the (C 1 -C 6 )alkyl are each optionally substituted with one or more halo or (C 1 -C 6 )alkoxy;
or a salt thereof,
when R c , is

then R 4 is

with R being 4-fluorobenzyl or benzyl,
when R 4 is carboxy, then R 1 is methoxymethyl, R 2 is H, R 3 is methoxymethyl, R 5 is methoxymethyl, and R 6 and R 7 taken together form —C(CH 3 ) 2 − .

2. The compound of claim 1 , wherein R 1 is H, methoxymethyl,

3. The compound of claim 1 , wherein R 2 is H.

4. The compound of claim 1 , wherein R 3 is H or methoxymethyl.

5. The compound of claim 1 , wherein R 4 is 1,2-dihydroxyethyl, formyl, cyano, hydroxymethyl, ethynyl, carboxy, 2,2,2-trifluoro-1-hydroxyethyl, hydroximinomethyl,

6. The compound of claim 1 , wherein R 5 is H or methoxymethyl.

7. The compound of claim 1 , wherein R 6 is H.

8. The compound of claim 1 , wherein R 7 is H.

9. The compound of claim 1 , wherein R 6 and R 7 taken together form —C(CH 3 ) 2 − .

10. The compound of claim 1 , wherein the compound is not one of the compounds:
4-((3R,3aR,5R,5bR,9aR,11S,12aS,14bS)-5,12a,14b-trihydroxy-11-(((3aR,4R,6S,7S,7aR)-7-hydroxy-2,2,6-trimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)oxy)-3a,8,8-trimethylhexadecahydro-1H-cyclopenta[7,8]phenanthro[4,4a-d][1,3]dioxin-3-yl)furan-2(5H)-one (1);
(2R,3R,4R,5S,6S)-2-(((1R,3S,5S,10R,11R,13R,14S,17R)-1,11-diacetoxy-10-(acetoxymethyl)-5,14-dihydroxy-13-methyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (1a); or
4-((3R,3aR,5R,5bR,9aR,11S,12aS,14bS)-5,11,12a,14b-tetrahydroxy-3a,8,8-trimethylhexadecahydro-1H-cyclopenta[7,8]phenanthro[4,4a-d][1,3]dioxin-3-yl)furan-2(5H)-one (12).

11. A compound selected from the group consisting of:
4-((3R,3aR,5R,5bR,9aR,11S,12aS,14bS)-12a,14b-dihydroxy-5-(methoxymethoxy)-11-(((3aR,4R,6S,7S,7aR)-7-(methoxymethoxy)-2,2,6-trimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)oxy)-3a,8,8-trimethylhexadecahydro-1H-cyclopenta[7,8]phenanthro[4,4a-d][1,3]dioxin-3-yl)furan-2(5H)-one (2);
(3S,3aR,5R,5bR,9aR,11S,12aS,14bS)-3-(1,2-dihydroxyethyl)-5-(methoxymethoxy)-11-(((3aR,4R,6S,7S,7aR)-7-(methoxymethoxy)-2,2,6-trimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)oxy)-3a,8,8-trimethylhexadecahydro-1H-cyclopenta[7,8]phenanthro[4,4a-d][1,3]dioxine-12a,14b-diol (3);
(3S,3aR,5R,5bR,9aR,11S,12aS,14bS)-12a,14b-dihydroxy-5-(methoxymethoxy)-11-(((3aR,4R,6S,7S,7aR)-7-(methoxymethoxy)-2,2,6-trimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)oxy)-3a,8,8-trimethylhexadecahydro-1H-cyclopenta[7,8]phenanthro[4,4a-d][1,3]dioxine-3-carbaldehyde (4);
(3S,3aR,5R,5bR,9aR,11S,12aS,14bS)-3-(1-hydroxyprop-2-yn-1-yl)-5-(methoxymethoxy)-11-(((3aR,4R,6S,7S,7aR)-7-(methoxymethoxy)-2,22,6-trimethyltetrahydro-3a-[1,3]dioxolo[4,5-c]pyran-4-yl)oxy)-3a,8,8-trimethylhexadecahydro-1H-cyclopenta[7,8]phenanthro[4,4a-d][1,3]dioxine-12a,14b-diol (5);
(3S,3aR,5R,5bR,9aR,11S,12aS,14bS)-3-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)(hydroxy)methyl)-5-(methoxymethoxy)-11-(((3aR,4R,6S,7S,7aR)-7-(methoxymethoxy)-2,2,6-trimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)oxy)-3a,8,8-trimethylhexadecahydro-1H-cyclopenta[7,8]phenanthro[4,4a-d][1,3]dioxine-12a,14b-diol (6);
(3S,3aR,5R,5bR,9aR,11S,12aS,14bS)-3-((1-benzyl-1H-1,2,3-triazol-4-yl)(hydroxy)methyl)-5-(methoxymethoxy)-11-(((3aR,4R,6S,7S,7aR)-7-(methoxymethoxy)-2,2,6-trimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)oxy)-3a,8,8-trimethylhexadecahydro-1H-cyclopenta[7,8]phenanthro[4,4a-d][1,3]dioxine-12a,14b-diol (7);
(1R,3S,5S,10R,11R,13R,14S,17S)-17-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)(hydroxy)methyl)-10-(hydroxymethyl)-13-methyl-3-(((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthrene-1,5,11,14-tetraol (8);
(1R,3S,5S,10R,11R,13R,14S,17S)-17-((1-benzyl-1H-1,2,3-triazol-4-yl)(hydroxy)methyl)-10-(hydroxymethyl)-13-methyl-3-(((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthrene-1,5,11,14-tetraol (9);
(3S,3aR,5R,5bR,9aR,11S,12aS,14bS)-3-(hydroxymethyl)-5-(methoxymethoxy)-11-(((3aR,4R,6S,7S,7aR)-7-(methoxymethoxy)-2,2,6-trimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)oxy)-3a,8,8-trimethylhexadecahydro-1H-cyclopenta[7,8]phenanthro[4,4a-d][1,3]dioxine-12a,14b-diol (10);
(3S,3aR,5R,5bR,9aR,11S,12aS,14bS)-12a,14b-dihydroxy-5-(methoxymethoxy)-11-(((3aR,4R,6S,7S,7aR)-7-(methoxymethoxy)-2,2,6-trimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)oxy)-3a,8,8-trimethylhexadecahydro-1H-cyclopenta[7,8]phenanthro[4,4a-d][1,3]dioxine-3-carbonitrile (11);
4-((3R,3aR,5R,5bR,9aR,11S,12aS,14bS)-12a-hydroxy-5,11,14b-tris(methoxymeth

Assignees

• Blanco Gustavo
• Georg Gunda I
• Syeda Shameem Sultana
• Univ Kansas
• Univ Minnesota

Inventors

• Blanco Gustavo
• Georg Gunda I
• Syeda Shameem Sultana

Classifications

• C07C247/14

  with azido groups bound to carbon atoms of rings other than six-membered aromatic rings · CPC title

• C07J7/002

  not substituted in position 16 · CPC title

• C07J41/005

  the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives · CPC title

• C07D249/06

  with aryl radicals directly attached to ring atoms · CPC title

• C07C49/653

  polycyclic · CPC title