Prodrugs of substituted triazole derivatives and uses thereof

Patent metadata

Field	Value
Publication number	US-11298367-B2
Application number	US-201816758742-A
Country	US
Kind code	B2
Filing date	Oct 17, 2018
Priority date	Oct 24, 2017
Publication date	Apr 12, 2022
Grant date	Apr 12, 2022

Abstract

The present invention relates to prodrugs of 3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl ]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-[3-(trifluoromethyl)-pyridin-2-yl ]-1H-1,2,4-triazole-5-carboxamide, 3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl ]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-[2-(trifluoromethyl)-phenyl]-1H-1,2,4-triazole-5-carboxamide and 3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl ]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(3-chloropyridin-2-yl)-1H-1,2,4-triazole-5-carboxamide, to processes for the preparation of such compounds, to pharmaceutical compositions containing such compounds, and to the use of such compounds or compositions for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of renal and cardiovascular diseases.

First claim

The invention claimed is:

1. A compound of formula (I)

in which
R 1 represents a group of formula

in which
# represents the point of attachment to the 1,2,4-triazolyl-ring, And/Or a pharmaceutically acceptable salt thereof, solvate thereof and/or solvate of a salt thereof.

2. A compound of formula (I) according to claim 1 , wherein
R 1 represents a group of formula

in which
# represents the point of attachment to the 1,2,4-triazolyl-ring.

3. (2S)-3-[1-({5-Carbamoyl-1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-3-(4-chlorophenyl)-5-oxo-1,5-dihydro-4H-1, 2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl dihydrogen phosphate according to claim 1 of a formula below

And/or a pharmaceutically acceptable salt thereof, solvate thereof and/or solvate of a salt thereof.

4. (2S)-3-[1-({5-Carbamoyl-1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-3-(4-chlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl dihydrogen phosphate according to claim 1 of a formula below

5. Process for preparing a compound of formula (I) and/Or a pharmaceutically acceptable salt thereof, solvate thereof andor solvate of a salt thereof,
according to claim 1 , wherein a compound of formula

is reacted with phosphorus oxychloride and hydrolysed to give a compound of formula (I),
or
[B] a compound of formula

is reacted with tetrabenzyl diphosphate and benzyl groups are removed under reducing conditions to give a compound of formula (I),
optionally followed, where appropriate, by converting the compound of formula (I) into respective pharmaceutically acceptable salt thereof, solvate thereof and/or solvate of a salt thereof by treatment with one or more corresponding solvents and/or bases.

6. Compound as defined in claim 1 for treatment and/or prevention of one or more diseases.

7. Compound as defined in claim 1 for treatment and/or prevention of one or more acute and/or chronic kidney diseases including diabetic nephropathy, acute and chronic heart failure, preeclampsia, peripheral arterial disease (PAD), coronary microvascular dysfunction (CMD), Raynaud's syndrome, dysmenorrhea, cardiorenal syndrome, hypervolemic and euvolemic hyponatremia, liver cirrhosis, ascites, edema and the syndrome of inadequate ADH secretion (SIADH).

8. A product comprising a compound as defined in claim 1 or a composition thereof for treatment and/or prevention of one or more acute and chronic kidney diseases including diabetic nephropathy, acute and chronic heart failure, preeclampsia, peripheral arterial disease (PAD), coronary microvascular dysfunction (CMD), Raynaud's syndrome dysmenorrhea, cardiorenal syndrome, hypervolemic and euvolemic hyponatremia, liver cirrhosis, ascites, edema and the syndrome of inadequate ADH secretion (SIADH).

9. Pharmaceutical composition comprising a compound as defined in claim 1 and one or more pharmaceutically acceptable excipients.

10. Pharmaceutical composition of claim 9 comprising one or more first active ingredients, optionally one or more compounds of formula (I), and one or more further active ingredients, optionally one or more additional therapeutic agents selected from the group consisting of diuretics, angiotensin All antagonists, ACE inhibitors, beta-receptor blockers, mineralocorticoid receptor antagonists, organic nitrates, NO donors, activators and stimulators of the soluble guanylate cyclase, and positive-inotropic agents, antiinflammatory agents, immunosuppressive agents, phosphate binders and/or compounds which modulate vitamin D metabolism.

11. The pharmaceutical composition as defined in claim 9 for treatment and/or prevention of one or more acute and chronic kidney diseases including diabetic nephropathy, acute and chronic heart failure, preeclampsia, peripheral arterial disease (PAD), coronary microvascular dysfunction (CMD), Raynaud's syndrome, dysmenorrhea, cardiorenal syndrome, hypervolemic and euvolemic hyponatremia, liver cirrhosis, ascites, edema and the syndrome of inadequate ADH secretion (SIADH).

12. Method for treatment and/or prevention of one or more acute and chronic kidney diseases including diabetic nephropathy, acute and chronic heart failure, preeclampsia, peripheral arterial disease (PAD) and coronary microvascular dysfunction (CMD), Raynaud's syndrome dysmenorrhea, cardiorenal syndrome, hypervolemic and euvolemic hyponatremia, liver cirrhosis, ascites, edema and the syndrome of inadequate ADH secretion (SIADH) in a human or other mammal, comprising administering to a human or other mammal in need thereof a therapeutically effective amount of one or more compounds as defined in claim 1 .

Assignees

• Bayer Ag
• Bayer Pharma AG

Inventors

• Collin-Kroepelin Marie-Pierre
• Kolkhof Peter
• Neubauer Thomas
• Fuerstner Chantal
• Pook Elisabeth
• Wittwer Matthias Beat
• Schmeck Carsten
• Wasnaire Pierre
• Schirmer Heiko
• Cernecka Hana
• Droebner Karoline
• Tinel Hanna
• Buchmueller Anja
• Mondritzki Thomas
• Kretschmer Axel
• Lustig Klemens
• Fricke Robert
• Levilain Guillaume
• Krenz Ursula
• Witowski Norbert

Classifications

• A61P9/00 Primary

  Drugs for disorders of the cardiovascular system · CPC title

• C07F9/65583 Primary

  each of the hetero rings containing nitrogen as ring hetero atom · CPC title

• A61P13/12

  of the kidneys · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• A61K31/675 Primary

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title