US 7,320,993 B1
Aryl-substituted pyridylalkane, alkene, and alkine carboxamides useful as cytostatic useful as cytostatic and immuosuppressive agents
Elfi Biedermann, Vaterstetten (Germany); Max Hasmann, Neuried (Germany); Roland Löser, Feldafing (Germany); Benno Rattel, Munich (Germany); Friedemann Reiter, Putzbrunn (Germany); Barbara Schein, Neufahrn (Germany); Klaus Seibel, Gräfelfing (Germany); Klaus Vogt, Munich (Germany); Katja Wosikowski, Poing (Germany); and Isabel Schemainda, Munich (Germany)
Assigned to Astellas Deutschland GmbH, Munich (Germany)
Filed on Jun. 16, 2000, as Appl. No. 9/596,086.
Application 09/596086 is a continuation of application No. PCT/EP98/08272, filed on Dec. 16, 1998.
Claims priority of application No. 197 56 261 (DE), filed on Dec. 17, 1997.
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/44 (2006.01); A61P 31/00 (2006.01); A61P 35/00 (2006.01); C07D 211/00 (2006.01); C07D 213/00 (2006.01)
U.S. Cl. 514—357  [514/89; 514/344; 514/348; 514/349; 514/350; 514/351; 514/352; 514/354; 514/355; 514/356; 546/22; 546/24; 546/285; 546/286; 546/287; 546/288; 546/289; 546/290; 546/296; 546/297; 546/300; 546/309; 546/310; 546/312; 546/315; 546/316; 546/318; 546/321; 546/322; 546/323; 546/326; 546/328; 546/330; 546/332; 546/335; 546/337] 18 Claims
 
1. A pyridylalkane, pyridylalkene or pyridylalkine acid amide compound of formula (I)

OG Complex Work Unit Drawing
wherein
R1 is selected from the group consisting of hydrogen, halogen, cyano, C1-C6-alkyl, C3-C6-alkenyl, C2-C6-alkinyl, trifluoromethyl, C3-C8-cycloalkyl, C1-C6-hydroxyalkyl, hydroxy, C1-C6-alkoxy, C3-C8-cycloalkyloxy, benzyloxy, C1-C7-alkanoyloxy, C1-C6-alkylthio, C2-C7-alkoxycarbonyl, aminocarbonyl, C2-C7-alkylaminocarbonyl, C3-C13-dialkylaminocarbonyl, carboxy, phenyl, phenoxy, phenylthio, pyridyloxy, pyridylthio, and NR4R5, wherein
R4 and R5 are selected independently of each other from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, benzyl and phenyl;
R2 is selected from the group consisting of hydrogen, halogen, cyano, C1-C6-alkyl, trifluoromethyl, hydroxy, C1-C6-alkoxy and benzyloxy;
R3 is selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, hydroxy, C1-C6-alkoxy and benzyloxy;
k is 0 or 1;
A is —CH═CH—;
D is selected from the group consisting of
C3-C12-alkylene,
a substituted C3-C12-alkylene which is substituted once or twice by C1-C6-alkyl, hydroxy,
C1-C6-alkoxy or phenyl,
C3-C12-alkenylene,
a substituted C3-C12-alkenylene which is substituted once or twice by C1-C6-alkyl, hydroxy, C1-C6-alkoxy or phenyl,
C5-C12-alkadienylene,
a substituted C5-C12-alkadienylene which is substituted once or twice by C1-C6-alkyl, hydroxy, C1-C6-alkoxy or phenyl,
C3-C12-alkinylene,
a substituted C3-C12-alkinylene which is substituted once or twice by C1-C6-alkyl, hydroxy,
C1-C6-alkoxy or phenyl,
C5-C12-alkeninylene,
a substituted C5-C12-alkeninylene which is substituted once or twice by C1-C6-alkyl, hydroxy, C1-C6-alkoxy or phenyl,
C3-C12-alkenylene or C3-C12-alkinylene, wherein, with the exception of the (G)-terminal methylene group in the C3-C12-alkenylene or C3-C12-alkinylene, one to three methylene units in the C3-C12-alkenylene or C3-C12-alkinylene are isosterically replaced by O, S, NR7, CO, SO or SO2, and
C3-C12-alkylene, wherein, with the exception of the G-terminal methylene group in the C3-C12 alkylene, one to three methylene units in the C3-C12 alkylene are isosterically replaced by O, S, CO, SO, or SO2;
R7 is hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C1-C6-acyl, or C1-C6-alkanesulfonyl;
G is G1 or G2 wherein G must contain at least one aromatic ring, wherein
G1 is —(CR9R10)m—R8;
and
m is 0 or 1;
R8 is selected from the group consisting of benzyl, diphenylmethyl, phenyl,
anellated bi- and tricyclic aromatic or partially hydrogenated carbocyclic ring systems with 8 to 18 ring atoms, and at least one aromatic ring, wherein the linkage can occur over an aromatic or a hydrogenated ring and either directly or over a methylene group;
R9 is selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C2-C6-alkinyl, benzyl, phenyl,
anellated bi- and tricyclic aromatic ring systems with 8 to 18 ring atoms, and at least one aromatic ring, wherein the linkage can occur over an aromatic ring and either directly or over a methylene group;
R10 is the same as R9, but is selected independently thereof, or is hydroxy;
G2 is ═CR8R9
which is bound to D by means of a double bond, wherein R8 and R9 have the above meaning;
and wherein aromatic ring systems in the substitutents R1, R2, R3, R4, R5, R8, R9, R10, and ring system ═CR8R9 may be substituted independently from each other by one to three of the same or different groups independently selected from the group consisting of halogen, cyano, C1-C6-alkyl, trifluoromethyl, C3-C8-cycloalkyl, benzyl, phenyl, hydroxy, C1-C6-hydroxyalkyl, C1-C6-alkoxy, C1-C6-alkoxy entirely or partially substituted by fluorine, benzyloxy, phenoxy, mercapto, C1-C6-alkylthio, phenylthio, sulfo, carboxy, C2-C7-carboxyalkyl, C3-C7-carboxyalkenyl, C2-C7-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, C1-C6-aminoalkyl, mono-C1-C6-alkylamino, di-(C1-C6-alkyl)amino and, for two adjacent residues on the aromatic ring, methylenedioxy; and
wherein alkyl residues in the group G can be substituted by one or two of the same or different groups selected from the group consisting of hydroxy, carboxy, C2-C7-alkoxycarbonyl, benzyloxycarbonyl, amino, mono-C1-C6-alkylamino and di-(C1-C6-alkyl)amino;
the cis- and trans-isomers, E- and Z-isomers including the corresponding enantiomers, diastereomers and other isomers, the tautomers and their acid addition salts including their hydrates.