Substituted phenylalanine derivatives

Patent metadata

Field	Value
Publication number	US-2016237045-A1
Application number	US-201415024939-A
Country	US
Kind code	A1
Filing date	Sep 24, 2014
Priority date	Sep 26, 2013
Publication date	Aug 18, 2016
Grant date	—

Abstract

The invention relates to substituted phenylalanine derivatives and to processes for preparation thereof, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially of cardiovascular disorders and/or severe perioperative blood loss.

First claim

1 . A compound of the formula

in which
R 1 represents a group of the formula

where # is the point of attachment to the nitrogen atom,
R 5 represents 5-membered heteroaryl,
where heteroaryl may be substituted by a substituent selected from the group consisting of oxo, chlorine, cyano, hydroxyl and C 1 -C 3 -alkyl,
in which alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of
hydroxy, amino, hydroxycarbonyl and methoxy, or
in which alkyl may be substituted by 1 to 7 fluorine substituents, or
in which alkyl is substituted by a substituent selected from the group consisting of hydroxy, amino, hydroxycarbonyl and methoxy, and in which alkyl is additionally substituted by 1 to 6 fluorine substituents,

R 6 represents hydrogen, fluorine or chlorine,
R 7 and R 8 together with the carbon atoms to which they are attached form a 5-membered heterocycle,
where the heterocycle may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, chlorine, cyano, hydroxyl, C 1 -C 3 -alkyl, pyrazolyl and pyridyl,
in which alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of hydroxy, amino, hydroxycarbonyl and methoxy, or
in which alkyl may be substituted by 1 to 7 fluorine substituents, or
in which alkyl is substituted by a substituent selected from the group consisting of hydroxy, amino, hydroxycarbonyl and methoxy, and in which alkyl is additionally substituted by 1 to 6 fluorine substituents,

R 9 represents hydrogen, fluorine or chlorine,

R 2 represents hydrogen, fluorine, chlorine, methyl or methoxy,
R 3a represents hydrogen, fluorine, chlorine, C 1 -C 4 -alkyl, methoxy or trifluoromethyl,
R 3b represents hydrogen or fluorine,
R 4 represents amino, cyano, hydroxymethyl, methyl, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylamino, C 1 -C 3 -alkoxycarbonyl, —S(O) 2 NR 10 R 11 , —C(O)NR 12 R 13 or —NR 14 (CO)R 15 ,
where alkoxy is substituted by 1 to 2 substituents independently of one another selected from the group consisting of fluorine, hydroxy, amino, hydroxycarbonyl, C 1 -C 3 -alkylamino, difluoromethyl, trifluoromethyl, —(OCH 2 CH 2 ) n —OCH 3 , —(OCH 2 CH 2 ) m —OH, morpholinyl, piperidinyl and pyrrolidinyl,
in which n is a number from 1 to 6,
in which m is a number from 1 to 6, and

where methyl is substituted by 5- or 6-membered heterocyclyl which is attached via a nitrogen atom, and
where
R 10 represents hydrogen, C 1 -C 3 -alkyl, C 3 -C 6 -cycloalkyl, benzyl or 4- to 8-membered heterocyclyl which is attached via a carbon atom,
R 11 represents hydrogen or C 1 -C 3 -alkyl, or
R 10 and R 11 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle,
in which the heterocycle may be substituted by 1 to 2 substituents selected independently from the group consisting of oxo, fluorine, hydroxyl, amino, hydroxycarbonyl, C 1 -C 4 -alkyl, C 1 -C 3 -alkylamino, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroeth-1-yl, C 1 -C 4 -alkoxycarbonyl, aminocarbonyl and C 1 -C 3 -alkylaminocarbonyl,
R 12 represents hydrogen, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, C 3 -C 6 -cycloalkyl, benzyl or 4- to 8-membered heterocyclyl which is attached via a carbon atom,
in which alkyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of fluorine, hydroxy, amino, hydroxycarbonyl, C 1 -C 3 -alkylamino, difluoromethyl, trifluoromethyl, —(OCH 2 CH 2 ) n —OCH 3 , —(OCH 2 CH 2 ) m —OH, morpholinyl, piperidinyl and pyrrolidinyl,
 in which n is a number from 1 to 6,
 in which m is a number from 1 to 6, and

in which cycloalkyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, fluorine, hydroxy, amino, C 1 -C 4 -alkyl and C 1 -C 3 -alkylamino,
in which alkyl and alkylamino for their part may be substituted by 1 to 5 fluorine substituents, and

in which heterocyclyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, fluorine, hydroxy, amino, hydroxycarbonyl, C 1 -C 4 -alkyl, C 1 -C 3 -alkylamino, C 1 -C 4 -alkoxycarbonyl, aminocarbonyl and C 1 -C 3 -alkylaminocarbonyl,
in which alkyl and alkylamino for their part may be substituted by 1 to 5 fluorine substituents, and

in which heterocyclyl may additionally be substituted by 1 to 4 substituents independently of one another selected from the group consisting of fluorine and methyl,

R 13 represents hydrogen or C 1 -C 3 -alkyl, or
R 12 and R 13 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle,
in which the heterocycle may be substituted by 1 to 2 substituents selected independently from the group consisting of oxo, fluorine, hydroxyl, amino, hydroxycarbonyl, C 1 -C 4 -alkyl, C 1 -C 3 -alkylamino, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroeth-1-yl, C 1 -C 4 -alkoxycarbonyl, aminocarbonyl and C 1 -C 3 -alkylaminocarbonyl,
in which alkyl for its part may be substituted by a hydroxy substituent,

R 14 represents hydrogen or C 1 -C 3 -alkyl,
R 15 represents C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, phenyl or 5- to 7-membered heterocyclyl,
in which alkyl may be substituted by a substituent selected from the group consisting of C 1 -C 3 -alkylamino and —NH(CO)CH 2 NH(CO)CH 2 NH 2 ,

or one of the salts thereof, solvates thereof or solvates of the salts thereof.

2 . The compound of claim 1 , characterized in that
R 1 represents a group of the formula

where # is the point of attachment to the nitrogen atom,
R 5 represents 5-membered heteroaryl,
R 6 represents hydrogen

R 2 represents hydrogen
R 3a represents hydrogen,
R 3b represents hydrogen,
R 4 represents amino, hydroxymethyl, —S(O) 2 NR 10 R 11 , —C(O) NR 12 R 13 or —NR 14 (CO)R 15 ,
where
R 10 and R 11 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle,
R 12 represents methyl, ethyl or 4- to 8-membered heterocyclyl which is attached via a carbon atom,
R 3 represents hydrogen, methyl or ethyl, or
R 12 and R 13 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle,
R 14 represents hydrogen
R 15 represents C 1 -C 4 -alkyl or 5- to 7-membered heterocyclyl,
in which alkyl may be substituted by a substituent selected from the group consisting of C 1 -C 3 -alkylamino and —NH(CO)CH 2 NH(CO)CH 2 NH 2 ,

or one of the salts thereof, solvates thereof or solvates of the salts thereof.

3 . The compound of claim 1 , characterized in that
R 1 represents a group of the formula

where # is the point of attachment to the nitrogen atom,
R 5 is tetrazolyl,
R 6 represents hydrogen

R 2 represents hydrogen
R 3a represents hydrogen,
R 3b represents hydrogen,
R 4 represents amino, hydroxymethyl or —C(O)NR 12 R 13 ,
where
R 12 represents methyl, ethyl or piperidinyl which is attached via a carbon atom,
R 13 represents hydrogen, methyl or ethyl, or
R 12 and R 13 together with the nitrogen ato

Assignees

• Bayer Pharma AG
• Bayer Pharma AG

Inventors

• Röhn Ulrike
• Ellermann Manuel
• Strassburger Julia
• Wendt Astrid
• Röhrig Susanne
• Webster Robert Alan
• Schmidt Martina Victoria
• Tersteegen Adrian
• Beyer Kristin
• Schäfer Martina
• Buchmüller Anja
• Gerdes Christoph
• Sperzel Michael
• Sandmann Steffen
• Heitmeier Stefan
• Hillisch Alexander
• Ackerstaff Jens
• Terjung Carsten

Classifications

• C07D405/12

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

• C07D401/12

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

• C07D249/08

  1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• C07D257/04 Primary

  Five-membered rings · CPC title