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US 8,772,492 B2Granted
Substituted isoquinoline and isoquinolinone derivatives
AssigneeSanofi
InventorsOliver Plettenburg, Katrin Lorenz, Jochen Goerlitzer, Matthias Lohn
Life of this patent
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Abstract
The invention relates to 6-substituted isoquinoline and isoquinoline derivatives of the formula (I) useful for the treatment and/or prevention of diseases associated with Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase, and compositions containing such compounds.
Claims48
A compound of the formula (I)
- wherein
- R1 is H, OH or NH2
- R2 is
- (C6-C10)aryl,
- (C7-C8)alkyl,
- (C2-C6)alkenyl,
- (C2-C6)alkynyl,
- (C1-C6)alkylene-C(O)NH2,
- (C1-C6)alkylene-C(O)NH—(C1-C6)alkyl,
- (C1-C6)alkylene-C(O)N[(C1-C6)alkyl]2,
- (C1-C6)alkylene-C(O)O—(C1-C6)alkyl,
- C(O)O—(C1-C6)alkyl,
- C(O)(C1-C6)alkyl,
- C(O)NH—(C1-C6)alkyl,
- C(O)NHR′,
- C(O)—NH(C2-C6)alkenyl,
- C(O)—NH(C2-C6)alkynyl,
- C(O)—NH(C1-C6)alkylene-R′,
- C(O)N[(C1-C6)alkyl]2 or
- R2 is (C1-C6)alkyl, provided that in said alkyl residue at least one hydrogen is substituted by OH, OCH3, COOH, COOCH3, NH2, NHCH3, N(CH3)2, CONH2, CONHCH3 or CON(CH3)2;
- or
- R2 is a (C1-C4)alkylene bound to the cyclic amine, in which the (C1-C4) alkylene forms a second bond to a different carbon atom of the cyclic amine ring and forms, together with carbon atoms of cyclic amine, a second, 4-8 membered ring;
- R3 is
- H,
- halogen,
- (C1-C6)alkyl,
- (C1-C6)alkylene-R′,
- OH,
- O—R″,
- NH2,
- NHR″,
- NR″R″ or
- NH—C(O)—R″,
- R4 is
- H,
- halogen,
- hydroxy,
- CN,
- (C1-C6)alkyl;
- R5 is
- H,
- halogen,
- CN,
- NO2,
- (C1-C6)alkyl,
- (C2-C6)alkenyl,
- CH(OH)—(C1-C6)alkyl,
- NH2,
- NH—SO2H,
- NH—SO2—(C1-C6)alkyl,
- NH—C(O)—(C1-C6)alkyl,
- C(O)N[(C1-C6)alkyl]2,
- C(O)OH, or
- C(O)O—(C1-C6)alkyl;
- R6 is
- H,
- R′,
- (C1-C8)alkyl,
- (C1-C6)alkylene-R′,
- (C1-C6)alkylene-O—(C1-C6)alkyl,
- (C1-C6)alkylene-O—R′,
- (C1-C6)alkylene-CH[R′]2,
- (C1-C6)alkylene-C(O)—R′,
- (C1-C6)alkylene-C(O)NH2,
- (C1-C6)alkylene-C(O)NH—R′,
- (C1-C6)alkylene-C(O)NH—(C1-C6)alkyl,
- (C1-C6)alkylene-C(O)N[(C1-C6)alkyl]2,
- (C1-C6)alkylene-C(O)N[R′]2;
- (C1-C6)alkylene-C(O)O—(C1-C6)alkyl,
- C(O)O—(C1-C6)alkyl,
- C(O)OR′,
- C(O)(C1-C6)alkyl,
- C(O)R′,
- C(O)NH—(C1-C6)alkyl,
- C(O)NHR′,
- C(O)N[(C1-C6)alkyl]R′
- C(O)N[(C1-C6)alkyl]2,
- C(O)—(C1-C6)alkylene-R′, or
- C(O)O(C1-C6)alkylene-R′;
- R7 is
- H,
- halogen,
- CN,
- NO2,
- (C1-C6)alkyl,
- O—(C1-C6)alkyl,
- (C2-C6)alkenyl,
- CH(OH)—(C1-C6)alkyl,
- NH2,
- NH—SO2H,
- NH—SO2—(C1-C6)alkyl,
- SO2—NH2,
- NH—C(O)—(C1-C6)alkyl,
- C(O)N[(C1-C6)alkyl]2,
- C(O)OH, or
- C(O)O—(C1-C6)alkyl;
- R8 is H, halogen or (C1-C6)alkyl;
- n is 1;
- m is 3;
- L is O—(CH2)p, S(CH2)p, S(O)(CH2)p, S(O)(CH2)p, SO2(CH2)p, NH(CH2)p, N(C1-C6)alkyl-(CH2)p, N(C3-C6)cycloalkyl-(CH2)p, N[CO(C1-C6)alkyl]-(CH2)p or N[(C1-C3)alkylene-R′]-(CH2)p;
- p is 0, 1, 2, 3, or 4;
- R′ is
- (C3-C8)cycloalkyl,
- (C5-C10)heterocyclyl,
- (C6-C10)aryl;
- R″ is
- (C3-C8)cycloalkyl,
- (C5-C10)heterocyclyl,
- (C6-C10)aryl,
- (C1-C6)alkyl,
- (C1-C6)alkylene-R′,
- (C1-C6)alkylene-O—(C1-C6)alkyl,
- (C1-C6)alkylene-O—R′, or
- (C1-C6)alkylene-NRxRy;
- and
- Rx and Ry are independently of each other
- (C1-C6)alkyl,
- (C5-C10)heterocyclyl,
- (C6-C10)aryl,
- (C1-C4)alkylene-(C5-C10)heterocyclyl,
- (C1-C4)alkylene-(C6-C10)aryl,
- (C1-C4)alkylene-NH(C1-C6)alkyl,
- (C1-C4)alkylene-N[(C1-C6)alkyl]2,
- (C1-C4)alkylene-N[(C6-C10)aryl]2, or
- (C1-C4)alkylene-N[(C5-C10)heterocyclyl]2;
- wherein in residues R2, R4, R5, R6, R7 and R8 as alkyl, alkylene or cycloalkyl can optionally be substituted one or more times by OH, OCH3, COOH, COOCH3, NH2, NHCH3, N(CH3)2, CONH2, CONHCH3 or CON(CH3)2;
- wherein in residues R2 to R8 as alkyl or alkylene can optionally be substituted one or more times by halogen;
- wherein in residues R2, R3, R6 as (C6-C10)aryl and (C5-C10)heterocyclyl are unsubstituted or substituted one or more times by suitable groups independently selected from halogen, OH, NO2, N3, CN, C(O)—(C1-C6)alkyl, COOH, COO(C1-C6)alkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2, (C1-C6)alkyl, (C1-C6)alkylene-OH, (C1-C6)alkylene-NH2, (C1-C6)alkylene-NH(C1-C6)alkyl, (C1-C6)alkylene-N[(C1-C6)alkyl]2, (C2-C6)alkenyl, (C2-C6)alkynyl, O—(C1-C6)alkyl, O—C(O)—(C1-C6)alkyl, PO3H2, SO3H, SO2—NH2, SO2NH(C1-C6)alkyl, SO2N[(C1-C6)alkyl]2, S—(C1-C6)alkyl;
- SO—(C1-C6)alkyl, SO2—(C1-C6)alkyl, SO2—N═CH—N[(C1-C6)alkyl]2, C(NH)(NH2), NH2, NH—(C1-C6)alkyl, N[(C1-C6)alkyl]2, NH—C(O)—(C1-C6)alkyl, NH—C(O)O—(C1-C6)alkyl, NH—SO2—(C1-C6)alkyl, N(C1-C6)alkyl-C(O)—(C1-C6)alkyl, N(C1-C6)alkyl-C(O)O—(C1-C6)alkyl, N(C1-C6)alkyl-C(O)—NH—(C1-C6)alkyl];
- or
- stereoisomeric form thereof and/or tautomeric form thereof and/or pharmaceutically acceptable salt thereof.
128 more elements
A compound selected from the group consisting of
- (2R,4R)-4-(Isoquinolin-6-yloxy)-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester,
- (2R,4R)-4-(Isoquinolin-6-yloxy)-2-o-tolylcarbamoyl-piperidine-1-carboxylic acid tert-butyl ester,
- (2R,4R)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid o-tolylamide,
- (2R,4R)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid isobutyl-amide,
- (2R,4R)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid 3-methoxy-benzylamide (11),
- (2R,4R)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid 2-chloro-benzylamide (12),
- (2R,4R)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid phenethyl-amide,
- (2R,4R)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid (3-methoxy-propyl)-amide,
- (2R,4R)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid (2-hydroxy-ethyl)-amide,
- (2R,4R)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid (furan-2-ylmethyl)-amide,
- (2S,4S)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid (furan-2-ylmethyl)-amide,
- (2S,4S)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid (3-methoxy-propyl)-amide,
- (2S,4S)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid (pyridin-2-ylmethyl)-amide,
- (2S,4S)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid prop-2-ynylamide,
- (2S,4S)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid phenethyl-amide,
- (2S,4S)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid 2-chloro-benzylamide,
- (2S,4S)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid isobutyl-amide,
- 6-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-isoquinoline, and
- 6-(1-benzyl-4-phenyl-piperidin-4-yloxy)-7-chloro-isoquinolin-1-one, or
- stereoisomeric form thereof and/or tautomeric form thereof and/or pharmaceutically acceptable salt thereof.
17 more elements
A compound selected from the group consisting of
- 6-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-2H-isoquinolin-1-one,
- 6-(8-Aza-bicyclo[3.2.1]oct-3-yloxy)-7-chloro-2H-isoquinolin-1-one,
- 6-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-2H-isoquinolin-1-one,
- 7-Chloro-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-2H-isoquinolin-1-one,
- 7-Methyl-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-2H-isoquinolin-1-one, and
- N6-(4-Amino-4-phenyl-cyclohexyl)-isoquinoline-1,6-diamine, or
- stereoisomeric form thereof and/or tautomeric form thereof and/or pharmaceutically acceptable salt thereof.
4 more elements
Dependencies are inferred from the claim text.