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US 2007/0179139 A1Published application
Substituted aminodicarboxylic acid derivatives having pharmaceutical properties
AssigneeBayer Aktiengesellschaft
InventorsCristina Alonso-Alija, Michael Harter, Michael Hahn, Josef Pernerstorfer, Stefan Weigand, Johannes-Peter Stasch, Frank Wunder
Life of this patent
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Abstract
The invention relates to compounds of formula (I) and their salts and stereoisomers in which the variables are as defined in the description and claims, for producing medicaments used in the treatment of cardiovascular and other diseases. Such compounds, processes for preparing them, compositions containing them, and methods of using them are claimed.
Claims14
A compound of the formula (I)
- where
- Z represents a phenyl ring which is fused with a saturated, partially unsaturated or aromatic carba- or heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O or with a partially unsaturated or aromatic heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the group consisting of S, N and/or O,
- V is missing or represents O, NR4, NR4CONR4, NR4CO, NR4SO2, COO, CONR4or S(O)o,
- where
- R4 independently of any other radical R4 optionally present represents hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or arylalkyl having 7 to 18 carbon atoms, where the aryl radical for its part may be mono- or polysubstituted by halogen, alkyl, alkoxy having up to 6 carbon atoms,
- o represents 0, 1 or 2,
- Q is missing or represents straight-chain or branched alkylene, straight-chain or branched alkenediyl or straight-chain or branched alkynediyl having in each case up to 12 carbon atoms, which radicals may in each case comprise one or more groups selected from the group consisting of O, S(O)p, NR5, CO, NR5SO2 or CONR5 and which may be mono- or polysubstituted by halogen, hydroxyl or alkoxy having up to 4 carbon atoms, where optionally any two atoms of the above chain may be attached to one another forming a three- to eight-membered ring,
- where
- R5 represents hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms which may be substituted by halogen or alkoxy having up to 4 carbon atoms,
- p represents 0, 1 or 2,
- Y represents hydrogen, NR8R9, aryl having 6 to 10 carbon atoms, an aromatic or saturated heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the group consisting of S, N and O or straight-chain or branched cycloalkyl having 3 to 8 carbon atoms, which may also be attached via N,
- where the cyclic radicals may in each case be mono- to trisubstituted by straight-chain or branched alkyl, straight-chain or branched alkenyl, straight-chain or branched alkynyl, straight-chain or branched alkoxy, straight-chain or branched haloalkyl, straight-chain or branched haloalkoxy having in each case up to 8 carbon atoms, straight-chain or branched cycloalkyl having 3 to 8 carbon atoms, halogen, hydroxyl, CN, SR6, NO2, NR8R9, NR7COR10, NR7CONR7R10 or CONR11R12,
- where
- R6 represents hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, straight-chain or branched haloalkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
- R7 independently of any other radical R7 optionally present represents hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
- R8, R9, R11 and R12 independently of one another represent hydrogen, straight-chain or branched alkyl, straight-chain or branched alkenyl having up to 8 carbon atoms, aryl having 6 to 10 carbon atoms, an aromatic heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the group consisting of S, N and O, arylalkyl having 8 to 18 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or a radical of the formula SO2R13, where the aryl radical for its part may be mono- or polysubstituted by halogen, hydroxyl, CN, NO2, NH2, NHCOR7, alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms,
- or two substituents selected from R8 and R9 or R10 and R12 may be attached to one another forming a five- or six-membered ring which may contain O or N,
- where
- R13 represents straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, where the aryl radical for its part may be mono- or polysubstituted by halogen, CN, NO2, alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms,
- R10 represents hydrogen, straight-chain or branched alkyl having up to 12 carbon atoms, straight-chain or branched alkenyl having up to 12 carbon atoms, aryl having 6 to 10 carbon atoms, an aromatic heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the group consisting of S, N and O or cycloalkyl having 3 to 8 carbon atoms, which may optionally furthermore be substituted by halogen, hydroxyl, CN, NO2, NH2, NHCOR7, alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms;
- and/or the cyclic radicals may in each case be mono- to trisubstituted by aryl having 6 to 10 carbon atoms, a saturated carbocycle having 6 to 10 carbon atoms, an aromatic or saturated heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the group consisting of S, N and O, which may also be attached via N,
- which may be attached directly or via a group selected from the group consisting of O, S, SO, SO2, NR7, SO2NR7, CONR7, straight-chain or branched alkylene, straight-chain or branched alkenediyl, straight-chain or branched alkyloxy, straight-chain or branched oxyalkyloxy, straight-chain or branched sulfonylalkyl, straight-chain or branched thioalkyl having in each case up to 8 carbon atoms and which may be mono- to trisubstituted by straight-chain or branched alkyl, straight-chain or branched alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or branched haloalkyl, straight-chain or branched haloalkoxy, carbonylalkyl or straight-chain or branched alkenyl having in each case up to 6 carbon atoms, halogen, SR6, CN, NO2, NR8R9, CONR15R16 or NR14COR17,
- where
- R14 represents hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
- R15, R16 independently of one another represent hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or a radical of the formula SO2R18, where the aryl radical for its part may be mono- or polysubstituted by halogen, hydroxyl, CN, NO2, NH2, NHCOR7, alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms,
- where
- R18 represents straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, where the aryl radical for its part may be mono- or polysubstituted by halogen, hydroxyl, CN, NO2, NH2, NHCOR7, alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms,
- and
- R17 represents hydrogen, straight-chain or branched alkyl having up to 12 carbon atoms, straight-chain or branched alkenyl having up to 12 carbon atoms, aryl having 6 to 10 carbon atoms, an aromatic heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the group consisting of S, N and O or cycloalkyl having 3 to 8 carbon atoms, which may optionally furthermore be substituted by halogen, hydroxyl, CN, NO2, NH2, NHCOR7, alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms;
- and/or the cyclic radicals may be fused with an aromatic or saturated carbocycle having 1 to 10 carbon atoms or an aromatic or saturated heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the group consisting of S, N and O,
- R3 represents hydrogen, halogen, straight-chain or branched alkyl which may optionally carry one or more substituents from the group consisting of C1-6-alkoxy, NR19R20 and cycloalkyl having 3 to 8 carbon atoms, straight-chain or branched haloalkyl, straight-chain or branched alkoxy, or alkoxycarbonyl having in each case up to 4 carbon atoms, CN, NO2, NR19R20, SR17, SO2R17, cycloalkyl having 3 to 8 carbon atoms, haloalkoxy, haloalkoxy having up to 6 carbon atoms, cycloalkoxy having up to 14 carbon atoms, CONH2, CONR17R17, SO2NH2, SO2NR17R17, alkoxyalkoxy having up to 12 carbon atoms, NHCOOR17, NHCOR17, NHSO2R17, NHCONH2, OCONR17R17, OSO2R17, C2-12-alkenyl or C2-12-alkynyl,
- where
- R19 and R20 independently of one another represent hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
- m represents an integer from 1 to 4,
- W represents straight-chain or branched alkylene having up to 6 carbon atoms or straight-chain or branched alkenediyl having up to 6 carbon atoms which may in each case contain a group selected from the group consisting of O, S(O)q, NR21, CO or CONR21, or represents CO, NHCO or OCO,
- where
- q represents 0, 1 or 2,
- R21 represents hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
- U represents straight-chain or branched alkyl having up to 4 carbon atoms,
- A represents aryl having 6 to 10 carbon atoms or an aromatic heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the group consisting of S, N and O,
- which may optionally be mono- to trisubstituted by halogen, straight-chain or branched alkyl, straight-chain or branched haloalkyl, straight-chain or branched alkoxy, haloalkoxy or alkoxycarbonyl having up to 4 carbon atoms, CN, NO2 or NR22R23,
- where
- R22 and R23 in each case independently of one another represent hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, carbonylalkyl or sulfonylalkyl,
- R2 represents tetrazolyl, COOR24 or CONR25R26,
- where
- R24 [lacuna] hydrogen, alkyl having 1 to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms
- R25 and R26 in each case independently of one another represent hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or a radical of the formula SO2R27,
- or
- R25 and R26 together form a five- or six-membered ring which may contain N or O,
- where
- R27 represents straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, where the aryl radical for its part may be mono- or polysubstituted by halogen, CN, NO2, alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms,
- X represents straight-chain or branched alkylene having up to 12 carbon atoms or straight-chain or branched alkenediyl having up to 12 carbon atoms, which may in each case contain one to three groups selected from the group consisting of O, S(O)r, NR28, CO or CONR29, aryl and aryloxy having 6 to 10 carbon atoms, where the aryl radical for its part may be mono- or polysubstituted by halogen, CN, NO2, alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms, where optionally any two atoms of the abovementioned chains are attached to one another via an alkyl chain forming a three- to eight-membered ring,
- where
- r represents 0, 1 or 2,
- R28 represents hydrogen, alkyl having 1 to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
- R29 represents hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
- n represents 1 or 2;
- R1 represents tetrazolyl, COOR30 or CONR31R32,
- where
- R30 [lacuna] hydrogen, alkyl having 1 to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms
- R31 and R32 in each case independently of one another represent hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or a radical of the formula SO2R33,
- where
- R33 represents straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms,
- where the aryl radical for its part may be mono- or polysubstituted by halogen, CN, NO2, alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms,
- and its stereoisomers and salts.
62 more elements
A process for preparing compounds of the general formula (I), characterized in that
- [A] compounds of the formula (II)
- are reacted with compounds of the formula (III)
- E-X—R1 (III)
- where
- Z, R1, R2, R3, V, Q, Y, W, X, U, A and m are as defined above,
- E represents either a leaving group which is substituted in the presence of a base or an optionally activated hydroxyl function;
- or
- [B] compounds of the formula (IV)
- are reacted with compounds of the formula (V)
- where
- Z, R1, R2, R3, V, Q, Y, W, X, U, A and m are as defined above,
- E represents either a leaving group which is substituted in the presence of a base or an optionally activated hydroxyl function;
- or
- [C] compounds of the formula (VI)
- are reacted with compounds of the formula (VII)
- E-U-A-R2 (VII)
- where
- Z, R1, R2, R3, V, Q, Y, W, X, U, A and m are as defined above,
- E represents either a leaving group which is substituted in the presence of a base or an optionally activated hydroxyl function;
- or
- [D] compounds of the formula (VIII)
- where
- Va represents O or S and
- Z, R1, R2, R3, Y, Q, W, U, A, X and m are as defined above,
- are reacted with compounds of the formula (IX)
- where
- Q, Y are as defined above,
- E represents either a leaving group which is substituted in the presence of a base or an optionally activated hydroxyl function;
- or
- [E] compounds of the formula (X)
- where
- Z, R3, V, Q, Y, W, X, U, A and m are as defined above,
- R1b and R2b each independently of one another represent CN or COOAlk, where Alk represents a straight-chain or branched alkyl radical having up to 6 carbon atoms,
- are converted with aqueous solutions of strong acids or strong bases into the corresponding free carboxylic acids.
- or
- [F] compounds of the formula (XI)
- where
- Z, R1, R2, R3, V, Q, X, W, U, A and mare as defined above,
- L represents Br, I or the group CF3SO2—O,
- are reacted with compounds of the formula (XII)
- M-Z′ (XII)
- where
- M represents an aryl or heteroaryl radical, a straight-chain or branched alkyl, alkenyl or alkynyl radical or cycloalkyl radical or represents an arylalkyl, an arylalkenyl or an arylalkynyl radical,
- Z′ represents the groupings —B(OH)2, —CH≡CH, —CH═CH2 or —Sn(nBu)3
- in the presence of a palladium compound, if appropriate additionally in the presence of a reducing agent and further additives and in the presence of a base;
- or
- [G] compounds of the formula (XIII)
- where
- Ar represents an aryl or heteroaryl radical,
- E represents a leaving group which is substituted in the presence of a base.
- are reacted according to process D with compounds of the formula (VIII) and the resulting compounds of the formula (XIV)
- are hydrogenated with hydrogen in the presence of a catalyst.
49 more elements
A medicament, comprising at least one compound of the general formula (I) as claimed in any of the preceding claims.
The use of compounds of the formula (I) as claimed in any of the preceding claims for preparing a medicament for treating cardiovascular disorders.
The use of compounds of the general formula (I) as claimed in any of the preceding claims for preparing medicaments for treating angina pectoris, ischemias and heart failure.
The use of compounds of the general formula (I) as claimed in any of the preceding claims for preparing medicaments for treating hypertension, thromboembolic disorders, arteriosclerosis and venous diseases.
The use of compounds of the general formula (I) as claimed in any of the preceding claims for preparing medicaments for treating fibrotic disorders.
The use as claimed in claim 16, characterized in that the fibrotic disorder is fibrosis of the liver.
Dependencies are inferred from the claim text.