# US 11,298,367 B2 · Prodrugs of substituted triazole derivatives and uses thereof

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 11,298,367 B2
- Document ID: US11298367B2
- Status: Granted
- Kind: B2
- Application number: 16/758,742
- Filed: 2018-10-17
- Published: 2020-10-29
- Granted: 2022-04-12
- Earliest claimed: 2017-10-24
- Assignees: Bayer Aktiengesellschaft
- Applicants: Bayer Aktiengesellschaft; Bayer Pharma Aktiengesellschaft
- Inventors: Marie-Pierre Collin-Kroepelin; Peter Kolkhof; Thomas Neubauer; Chantal Fuerstner; Elisabeth Pook; Matthias Beat Wittwer; Carsten Schmeck; Pierre Wasnaire; Heiko Schirmer; Hana Cernecka; Karoline Droebner; Hanna Tinel; Anja Buchmueller; Thomas Mondritzki; Axel Kretschmer; Klemens Lustig; Robert Fricke; Guillaume Levilain; Ursula Krenz; Norbert Witowski
- Web page: https://patentgrep.com/patent/US11298367B2

## CPC

- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 13/12: of the kidneys
- C07D 401/14: containing three or more hetero rings
- C07F 9/65583: {each of the hetero rings containing nitrogen as ring hetero atom}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## 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.

## Claims

### Claim 1

A compound of formula (I)
in which
R1 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.

### Claim 2 (depends on 1)

A compound of formula (I) according to claim 1, wherein
R1 represents a group of formula
in which
# represents the point of attachment to the 1,2,4-triazolyl-ring.

### Claim 3 (depends on 1)

(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.

### Claim 4 (depends on 1)

(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

### Claim 5 (depends on 1)

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.

### Claim 6 (depends on 1)

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

### Claim 7 (depends on 1)

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).

### Claim 8 (depends on 1)

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).

### Claim 9 (depends on 1)

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

### Claim 10 (depends on 9)

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.

### Claim 11 (depends on 9)

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).

### Claim 12 (depends on 1)

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.