Indane derivatives and the use thereof as soluble guanylate cyclase activators

Patent metadata

Field	Value
Publication number	US-10316020-B2
Application number	US-201616063059-A
Country	US
Kind code	B2
Filing date	Dec 16, 2016
Priority date	Dec 18, 2015
Publication date	Jun 11, 2019
Grant date	Jun 11, 2019

Abstract

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof; a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

First claim

What is claimed is:

1. A compound according to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein
X is CH or N;
is a single bond or a double bond;
A is CH 2 , O or N(H);
Z is CR 4 or N with the proviso that A is not O when Z is N;
When X is CH then R is C 1 -C 4 alkoxy, amino, C 1 -C 4 alkylamino or di-C 1 -C 4 alkylamino; or
When X is N then R is C 1 -C 4 alkoxy or amino with the proviso that R is not C 1 -C 4 alkoxy, when A is NH and Z is CH;
R 1 is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy;
R 2 is C 3 -C 5 cycloalkyl, C 1 -C 4 alkyl or hydroxyC 1 -C 4 alkyl;
R 3 is hydrogen, halogen or C 1 -C 4 alkyl; and
R 4 is hydrogen, methyl or ethyl.

2. A compound according to Formula (Ia)

or a pharmaceutically acceptable salt thereof, wherein the bond is a single or double bond;
A is CH 2 , O or N(H);
Z is CR 4 or N with the proviso that A is not O when Z is N;
R is C 1 -C 4 alkoxy, amino, C 1 -C 4 alkylamino or diC 1 -C 4 alkylamino;
R 1 is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy;
R 2 is C 3 -C 5 cycloalkyl, C 1 -C 4 alkyl or hydroxyC 1 -C 4 alkyl;
R 3 is hydrogen, halogen or C 1 -C 4 alkyl; and
R 4 is hydrogen, methyl or ethyl.

3. The compound of claim 2 , wherein R is methoxy or amino.

4. The compound claim 2 , wherein R 1 is hydrogen, methyl or methoxy.

5. The compound according to claim 2 , wherein Z is N; and A is CH 2 or N(H).

6. The compound according to claim 2 , wherein R 2 is cyclopropyl or 1-hydroxyethyl.

7. The compound according to claim 2 , wherein R 3 is ethyl.

8. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
(+)-(R)-1-(3-(3-(4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-ethylbenzyl)-2,3-dihydro-1H-inden-4-yl)phenyl)-5-methoxy-1H-pyrazole-4-carboxylic acid;
(+)-1-(3-((R)-3-(3-ethyl-4-(1-((S)-2-hydroxypropanoyl)piperidin-4-yl)benzyl)-2,3-dihydro-1H-inden-4-yl)phenyl)-5-methoxy-1H-pyrazole-4-carboxylic acid;
(+)-(S)-1-(3-(3-((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-ethyl phenyl)amino)-2,3-dihydro-1H-inden-4-yl)phenyl)-5-methoxy-1H-pyrazole-4-carboxylic acid;
(+)-1-(3-(3-((3-ethyl-4-(1-((S)-2-hydroxypropanoyl)piperidin-4-yl)phenyl)amino)-2,3-dihydro-1H-inden-4-yl)phenyl)-5-methoxy-1H-pyrazole-4-carboxylic acid;
(+)-(S)-1-(3-(3-(4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-ethylphenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl)-5-methoxy-1H-pyrazole-4-carboxylic acid;
1-(3-((S)-3-(3-ethyl-4-(1-((S)-2-hydroxypropanoyl)piperidin-4-yl)phenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl)-5-methoxy-1H-pyrazole-4-carboxylic acid;
(+)-1-(5-(3-((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-ethylphenyl)amino)-2,3-dihydro-1H-inden-4-yl)-2-methylphenyl)-5-methoxy-1H-pyrazole-4-carboxylic acid;
(+)-1-(5-(3-((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-ethylphenyl)amino)-2,3-dihydro-1H-inden-4-yl)-2-methoxyphenyl)-5-methoxy-1H-pyrazole-4-carboxylic acid;
(+)-5-amino-1-(3-(3-((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-ethylphenyl)amino)-2,3-dihydro-1H-inden-4-yl)phenyl)-1H-pyrazole-4-carboxylic acid;
(+)-1-(3-(3-((1′-(cyclopropanecarbonyl)-2-ethyl-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridin]-6-yl)amino)-2,3-dihydro-1H-inden-4-yl)phenyl)-5-methoxy-1H-pyrazole-4-carboxylic acid; and
(enantiomer-2)-1-(3-(3-((4-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-3-ethylphenyl)amino)-2,3-dihydro-1H-inden-4-yl)phenyl)-5-(methylamino)-1H-pyrazole-4-carboxylic acid.

9. A compound according to Formula (I)

or a pharmaceutically acceptable salt thereof, wherein
is a single or double bond;
A is CH 2 , O or N(H);
Z is CR 4 or N, with the proviso that A is not O when Z is N;
R is C 1 -C 4 alkoxy or amino with the proviso that R is not C 1 -C 4 alkoxy, when A is NH and Z is CH;
R 1 is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy;
R 2 is C 3 -C 5 cycloalkyl, C 1 -C 4 alkyl or hydroxyC 1 -C 4 alkyl; and
R 3 is hydrogen, halogen or C 1 -C 4 alkyl; and
R 4 is hydrogen, methyl or ethyl.

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
(+)-1-(6-(3-(4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-ethylbenzyl)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-methoxy-1H-pyrazole-4-carboxylic acid;
(S)-1-(6-(3-(4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-ethylphenoxy)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-methoxy-1H-pyrazole-4-carboxylic acid;
1-(6-((S)-3-(3-ethyl-4-(1-((S)-2-hydroxypropanoyl)piperidin-4-yl)phenoxy)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-methoxy-1H-pyrazole-4-carboxylic acid;
(+)-5-amino-1-(6-(3-((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-ethylphenyl)amino)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-1H-pyrazole-4-carboxylic acid;
(S)-5-amino-1-(6-(3-(4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-ethylphenoxy)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-1H-pyrazole-4-carboxylic acid;
(+)-1-(6-(3-((1′-(cyclopropanecarbonyl)-2-ethyl-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridin]-6-yl)amino)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-methoxy-1H-pyrazole-4-carboxylic acid; and
1-(6-((S or R)-3-((2-ethyl-1′-((S)-2-hydroxypropanoyl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridin]-6-yl)amino)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-methoxy-1H-pyrazole-4-carboxylic acid.

11. A pharmaceutical composition comprising a compound of claim 1 , or a salt thereof, and a pharmaceutically acceptable excipient.

12. A method of treating glaucoma and controlling intraocular pressure comprising: applying a therapeutically effective amount of a pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof to an affected eye of a patient.

13. The method of claim 12 , wherein said applying comprises applying using a technique selected from the group consisting of: topical ocular administration, periocular injection, sub-conjunctival injection, sub-tenon injection, intracameral injection, intravitreal injection, intracanalicular injection, implanting delivery device in the cul-de-sac, implanting delivery device adjacent to the sclera, implanting delivery device within the eye, oral administration, intravenous administration, subcutaneous administration, intramuscular administration, parenteral administration, dermal administration, and nasal administration.

14. The method of claim 12 wherein method further comprises administering to the affected eye of the patient a glaucoma treatment agent selected from the group consisting of beta-blockers, prostaglandin analogs, sGC stimulators, nitric oxide precursors, carbonic anhydrase inhibitors, α2 agonists, miotics, and neuroprotectants.

15. The method of claim 12 , wherein the method further comprises administering to the affected eye of the patient a PDE-V inhibitor.

16. The method of claim 15 wherein the method PDE-V inhibitor is selected from sildenafil, tadalafil and vardenafil.

17. A pharmaceutical composition comprising a compound of claim 1 , or a salt thereof, another therapeutic agent, and a pharmaceutically acceptable excipient.

18. A

Assignees

• Novartis Ag

Inventors

• Adams Christopher
• Ehara Takeru

Classifications

• A61P27/06

  Antiglaucoma agents or miotics · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D401/10 Primary

  linked by a carbon chain containing aromatic rings · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title