Substituted 1,2,4-triazine-3,5-diones and the use thereof as chymase inhibitors

Patent metadata

Field	Value
Publication number	US-2016287599-A1
Application number	US-201415035171-A
Country	US
Kind code	A1
Filing date	Nov 5, 2014
Priority date	Nov 8, 2013
Publication date	Oct 6, 2016
Grant date	—

Abstract

Substituted 1,2,4-triazine-3,5-dione derivatives, processes for their preparation, their use alone or in combinations for the treatment and/or prophylaxis of diseases, and their use for preparing medicaments for the treatment and/or prophylaxis of diseases.

First claim

1 . A compound of the formula (I)

in which
R 1 represents hydrogen or (C 1 -C 4 )-alkyl,
R 2 represents a group of the formula

where
* represents the point of attachment to the triazinedione nitrogen atom,
A represents —CH 2 —, —CH 2 —CH 2 —, —O—CH 2 —** or oxygen,
in which ** represents the point of attachment to the phenyl ring,
m represents a number 0, 1 or 2,
R 4 represents hydrogen, halogen, difluoromethyl, trifluoromethyl, (C 1 -C 4 )-alkyl, difluoromethoxy, trifluoromethoxy or (C 1 -C 4 )-alkoxy,

R 3 represents

where
# represents the point of attachment to the triazinedione nitrogen atom,
R 9 represents hydrogen,
R 10 represents hydrogen, halogen, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy,
R 11 represents (C 1 -C 4 )alkyl, (C 1 -C 4 )-alkoxy or —N(R 14 R 15 ), in which (C 1 -C 4 )-alkyl may be up to trisubstituted by halogen,
in which (C 1 -C 4 )-alkoxy may be substituted by a substituent selected from the group consisting of hydroxy, (C 1 -C 4 )-alkoxycarbonyl, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, aminocarbonyl, mono-(C 1 -C 4 )-alkyl aminocarbonyl and di-(C 1 -C 4 )-alkyl aminocarbonyl,
where
R 14 represents (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxycarbonyl or (C 1 -C 4 )-alkylaminocarbonyl,
in which (C 1 -C 4 )-alkylaminocarbonyl may be substituted by hydroxy or (C 1 -C 4 )-alkoxy,

R 15 represents hydrogen or (C 1 -C 4 )-alkyl,
or
R 11 represents 4- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl,
in which 4- to 7-membered heterocyclyl may be substituted by 1 to 3 sub stituents independently of one another selected from the group consisting of halogen, trifluoromethyl, (C 1 -C 4 )-alkyl, hydroxy, oxo, amino and (C 1 -C 4 )-alkoxycarbonyl,
in which 5- to 6-membered heteroaryl may be substituted by 1 or 2 sub stituents independently of one another selected from the group consisting of halogen, trifluoromethyl, (C 1 -C 4 )-alkyl, hydroxy, amino and (C 1 -C 4 )-alkoxycarbonyl,

R 12 represents hydrogen, halogen, cyano, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy,
R 13 represents hydrogen, halogen, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy,

or
R 3 represents

where
# represents the point of attachment to the triazinedione nitrogen atom, the ring Q represents 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl,
in which 5- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl may be substituted by 1 to 4 substituents independently selected from the group of halogen, difluoromethyl, trifluoromethyl, trideuteromethyl, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, oxo, hydroxyl, (C 1 -C 4 )-alkylcarbonyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl and (C 1 -C 4 )-alkyl sulfonyl,
in which (C 1 -C 6 )-alkyl and (C 3 -C 7 )-cycloalkyl may in turn be substituted by 1 to 3 substituents independently selected from the group of halogen, cyano, trifluoromethyl, (C 3 -C 7 )-cycloalkyl, hydroxyl, (C 1 -C 4 )-alkoxy and 4- to 7-membered heterocyclyl,
and
in which two (C 1 -C 6 )-alkyl radicals attached to a carbon atom of 5- to 7-membered heterocyclyl together with the carbon atom to which they are attached may form a 3- to 6-membered carbocycle,

R 16 represents halogen, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy,
n represents a number 0, 1, 2 or 3,

and the salts, solvates and solvates of the salts thereof.

2 . The compound of claim 1 of the formula (I), in which
R 1 represents hydrogen or (C 1 -C 4 )-alkyl,
R 2 represents a group of the formula

where
* represents the point of attachment to the triazinedione nitrogen atom,
A represents —CH 2 — or —CH 2 —CH 2 —,
m represents a number 0, 1 or 2,
R 4 represents hydrogen, fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl,

R 3 represents

where
# represents the point of attachment to the triazinedione nitrogen atom,
R 9 represents hydrogen,
R 10 represents hydrogen, halogen or (C 1 -C 4 )-alkoxy,
R 11 represents (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy or —N(R 14 R 15 ),
where
R 14 represents (C 1 -C 4 )-alkyl,
R 15 represents hydrogen or (C 1 -C 4 )-alkyl,

or
R 11 represents 5- or 6-membered heterocyclyl, in which 5- or 6-membered heterocyclyl may be substituted by 1 or 2 sub stituents independently of one another selected from the group consisting of trifluoromethyl, (C 1 -C 4 )-alkyl and oxo,
R 12 represents hydrogen,
R 13 represents hydrogen or (C 1 -C 4 )-alkyl,

or
R 3 represents a group of the formula

where
# represents the point of attachment to the triazinedione nitrogen atom,
G 1 represents C═O or SO 2 ,
G 2 represents CR 21A R 21B , NR 22 , O or S,
where
R 21A represents hydrogen, fluorine, (C 1 -C 4 )-alkyl or hydroxy,
R 21B represents hydrogen, fluorine, chlorine, (C 1 -C 4 )-alkyl or trifluoromethyl,
or
R 21A and R 21B together with the carbon atom to which they are attached form a 3- to 6-membered carbocycle,

R 22 represents hydrogen, (C 1 -C 6 )-alkyl or (C 3 -C 7 )-cycloalkyl,

R 19 represents fluorine or methyl,
n represents a number 0 or 1,
R 20 represents hydrogen, (C 1 -C 6 )-alkyl or (C 3 -C 6 )-cycloalkyl, and the salts, solvates and solvates of the salts thereof.

3 . The compound of claim 1 of the formula (I) in which
R 1 represents hydrogen, methyl or ethyl,
R 2 represents a group of the formula

where
* represents the point of attachment to the triazinedione nitrogen atom,
A represents —CH 2 — or —CH 2 —CH 2 —,
R 4 represents chlorine or trifluoromethyl,

R 3 represents

where
# represents the point of attachment to the triazinedione nitrogen atom,
R 9 represents hydrogen,
R 10 represents hydrogen,
R 11 represents methoxy or ethoxy,
or
R 11 represents a group of the formula

in which
## represents the point of attachment to the phenyl ring,
R 12 represents hydrogen,
R 13 represents hydrogen or methyl,

or
R 3 represents a group of the formula

where
# represents the point of attachment to the triazinedione nitrogen atom, and the salts, solvates and solvates of the salts thereof.

4 . A method of preparing the compound of claim 1 , in which
[A] a compound of the formula (II)
H 2 N—R 3   (II)

in which
R 3 is as defined above,
is diazotized in an inert solvent using sodium nitrite and a suitable acid to give a compound of the formula (II-1)

in which
R 3 has the meaning given above,
and the diazonium salt is, optionally in

Assignees

• Bayer Pharma AG

Inventors

• Fürstner Chantal
• Ackerstaff Jens
• Straub Alexander
• Meier Heinrich
• Tinel Hanna
• Zimmermann Katja
• Zubov Dmitry
• Schamberger Jens

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P19/00

  Drugs for skeletal disorders · CPC title

• A61P13/12

  of the kidneys · CPC title