Back to results
US 7,605,163 B2Granted
Benzoyl-piperazine derivatives
AssigneeHoffmann-La Roche Inc.
InventorsSynese Jolidon, Robert Narquizian, Matthias Heinrich Nettekoven, Roger David Norcross, Emmanuel Pinard, Henri Stalder
Life of this patent
Estimating the term…
Abstract
The invention relates to compounds of formula wherein the substituents are described herein. The compounds may be used in the treatment of illnesses based on the glycine uptake inhibitor, such as psychoses, pain, neurodegenerative disfunction in memory and learning, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer's disease.
Claims19
A compound of formula
- wherein
- Ar is unsubstituted or substituted aryl selected from the group consisting of phenyl, naphthyl, biphenyl, and indanyl, wherein the substituted aryl is substituted by one or more substituents selected from the group consisting of hydroxy, halogen, NO2, CN, (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n—(C1-C6)-alkoxy, (C1-C6)-alkoxy substituted by halogen, NR7R8, C(O)R9, SO2R10, and —C(CH3)═NOR7, or are substituted by a 5-membered aromatic heterocycle containing 1-4 heteroatoms selected from N and O, which is optionally substituted by (C1-C6)-alkyl;
- R1 is hydrogen or (C1-C6)-alkyl;
- R2 is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n—(C3-C7)-cycloalkyl optionally substituted by (C1-C6)-alkoxy or by halogen, CH(CH3)—(C3-C7)-cycloalkyl, (CH2)n+1—C(O)—R9, (CH2)n+1—CN, bicyclo[2.2.1]heptyl, (CH2)n+1—O—(C1-C6)-alkyl, (CH2)n-heterocycloalkyl, (CH2)n-aryl or (CH2)n-5 or 6-membered heteroaryl containing one, two or three heteroatoms selected from the group consisting of oxygen, sulphur or nitrogen wherein aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, halogen, (C1-C6)-alkyl and (C1-C6)-alkoxy;
- R3, R4 and R6 are each independently hydrogen, hydroxy, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or O—(C3-C6)-cycloalkyl;
- R5 is NO2, CN, C(O)R9 or SO2R10;
- R7 and R8 are each independently hydrogen or (C1-C6)-alkyl;
- R9 is (C1-C6)-alkoxy or NR7R8;
- R10 is (C1-C6)-alkyl optionally substituted by halogen, (CH2)n—(C3-C6)-cycloalkyl, (CH2)n—(C3-C6)-alkoxy, or (CH2)n-heterocycloalkyl;
- n is 0, 1, or 2;
- or a pharmaceutically acceptable acid addition salt thereof.
8 more elements
A compound of formula
- wherein
- Ar is substituted aryl, selected from the group consisting of phenyl, naphthyl, biphenyl, and indanyl wherein the substituted aryl is substituted by one or more substituents selected from the group consisting of hydroxy, halogen, NO2, CN, (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkoxy, (C1-C6)-alkoxy substituted by halogen, NR7R8, C(O)R9 and SO2R10;
- R1 is hydrogen or (C1-C6)-alkyl;
- R2 is (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen, (C3-C6)-cycloalkyl, heterocycloalkyl, (C1-C6)-alkyl-(C3-C6)-cycloalkyl, (C1-C6) -alkyl-heterocycloalkyl, (C1-C6) -alkyl-C(O)—R9, (C1-C6)-alkyl-CN, (C2-C6)-alkyl-O—R13, (C2-C6)-alkyl-NR7R8, aryl, 6-membered heteroaryl containing one, two or three nitrogen atoms, (C1-C6)-alkyl-aryl or (C1-C6)-alkyl-5 or -6-membered heteroaryl containing one, two or three heteroatoms selected from the group consisting of oxygen, sulphur or nitrogen wherein aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, halogen, (C1-C6)-alkyl and (C1-C6)-alkoxy;
- R3, R4 and R6 are each independently hydrogen, hydroxy, halogen, CN, (C1-C6)-alkyl, or (C1-C6)-alkoxy;
- R5 is NO2, CN, C(O)R9, SO2R10 or NR11R12;
- R7 and R8 are each independently hydrogen or (C1-C6)-alkyl;
- R9 is hydroxy, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy or NR7R8;
- R10 is (C1-C6)-alkyl, or (C3-C6)-cycloalkyl;
- R11 and R12 are each independently hydrogen, C(O)—(C1-C6)-alkyl, or SO2—(C1-C6)-alkyl, or form together with the N-atom to which they are attached a 5-membered heteroaryl group, optionally substituted by halogen, (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen or (C3-C6)-cycloalkyl;
- R13 is hydroxy, (C1-C6)-alkyl or (C3-C6)-cycloalkyl;
- or a pharmaceutically acceptable acid addition salt thereof.
9 more elements
A compound selected from the group consisting of
- 3-[4-(4-Cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-N-methyl-4-trifluoromethoxy-benzenesulfonamide,
- 3-[4-(4-cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-isobutoxy-N-methyl-benzenesulfonamide,
- 3-[4-(4-cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclopentyloxy-N-methyl-benzenesulfonamide,
- 3-[4-(4-cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclobutoxy-N-methyl-benzenesulfonamide,
- 3-[4-(4-cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclobutylmethoxy-N-methyl-benzenesulfonamide,
- 3-[4-(4-cyano-phenyl)-piperazine-1-carbonyl]-4-isobutoxy-N-methyl-benzenesulfonamide,
- 3-[4-(4-cyano-phenyl)-piperazine-1-carbonyl]-4-cyclopentyloxy-N-methyl-benzenesulfonamide,
- 3-[4-(4-cyano-phenyl)-piperazine-1-carbonyl]-4-cyclobutylmethoxy-N-methyl-benzenesulfonamide,
- 3-[4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-isobutoxy-N-methyl-benzenesulfonamide,
- 3-[4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-(2,2-dimethyl-propoxy)-N-methyl-benzenesulfonamide,
- 3-[4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-isopropoxy-N-methyl-benzenesulfonamide;
- 3-[4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclopentyloxy-N-methyl-benzenesulfonamide,
- 3-[4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclobutoxy-N-methyl-benzenesulfonamide,
- 3-[4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclopropylmethoxy-N-methyl-benzenesulfonamide,
- 3-[4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclobutylmethoxy-N-methyl-benzenesulfonamide,
- 3-[4-(4-acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-isobutoxy-N-methyl-benzenesulfonamide, and
- 3-[4-(4-acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-(2,2-dimethyl-propoxy)-N-methyl-benzenesulfonamide.
14 more elements
A compound selected from the group consisting of 3-[4-(4-acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclopentyloxy-N-methyl-benzenesulfonamide,
- 3-[4-(4-acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclobutoxy-N-methyl-benzenesulfonamide,
- 3-[4-(4-acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclopropylmethoxy-N-methyl-benzenesulfonamide,
- 4-isobutoxy-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,
- 4-(2,2-dimethyl-propoxy)-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide;
- 4-isopropoxy-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,
- 4-cyclopentyloxy-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,
- 4-cyclobutoxy-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,
- 4-cyclopropylmethoxy-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,
- 4-cyclobutylmethoxy-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,
- N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-4-(3,3,3-trifluoro-propoxy)-benzenesulfonamide,
- 3-[4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carbonyl]-N-methyl-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonamide,
- N-methyl-4-(2,2,2-trifluoro-ethoxy)-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide
- rac-N-methyl-4-(2,2,2-trifluoro-1-methyl-ethoxy)-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,
- rac-3-[4-(4-cyano-2,5-difluoro-phenyl)-piperazine-1-carbonyl]-N-methyl-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonamide, and
- rac-3-[4-(4-cyano-2,3-difluoro-phenyl)-piperazine-1-carbonyl]-N-methyl-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonamide.
12 more elements
A composition comprising one or more compounds of formula
- wherein
- Ar is unsubstituted or substituted aryl selected from the group consisting of phenyl, naphthyl, biphenyl, and indanyl, wherein the substituted aryl is substituted by one or more substituents selected from the group consisting of hydroxy, halogen, NO2, CN, (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n—(C1-C6)-alkoxy, (C1-C6)-alkoxy substituted by halogen, NR7R8, C(O)R9, SO2R10, and —C(CH3)═NOR7, or are substituted by a 5-membered aromatic heterocycle containing 1-4 heteroatoms selected from N and O, which is optionally substituted by (C1-C6)-alkyl;
- R1 is hydrogen or (C1-C6)-alkyl;
- R2 is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n—(C3-C7)-cycloalkyl optionally substituted by (C1-C6)-alkoxy or by halogen, CH(CH3)—(C3-C7)-cycloalkyl, (CH2)n+1—C(O)—R9, (CH2)n+1—CN, bicyclo[2.2.1]heptyl, (CH2)n+1—O—(C1-C6)-alkyl, (CH2)n-heterocycloalkyl, (CH2)n-aryl or (CH2)n-5 or 6-membered heteroaryl containing one, two or three heteroatoms selected from the group consisting of oxygen, sulphur or nitrogen wherein aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, halogen, (C1-C6)-alkyl and (C1-C6)-alkoxy;
- R3, R4 and R6 are each independently hydrogen, hydroxy, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or O—(C3-C6)-cycloalkyl;
- R5 is NO2, CN, C(O)R9 or SO2R10;
- R7 and R8 are each independently hydrogen or (C1-C6)-alkyl;
- R9 is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or NR7R8;
- R10 is (C1-C6)-alkyl optionally substituted by halogen, (CH2)n—(C3-C6)-cycloalkyl, (CH2)n—(C3-C6)-alkoxy, or (CH2)n-heterocycloalkyl;
- n is 0, 1, or 2;
- or a pharmaceutically acceptable acid addition salt thereof,
- and a pharmaceutically acceptable excipient.
9 more elements
A method of treating an schizophrenia, which method comprises administering to an individual an effective amount of one or more compounds of formula
- wherein
- Ar is unsubstituted or substituted aryl selected from the group consisting of phenyl, naphthyl, biphenyl, and indanyl, wherein the substituted aryl is substituted by one or more substituents selected from the group consisting of hydroxy, halogen, NO2, CN, (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n—(C1-C6)-alkoxy, (C1-C6)-alkoxy substituted by halogen, NR7R8, C(O)R9, SO2R10, and —C(CH3)═NOR7, or are substituted by a 5-membered aromatic heterocycle containing 1-4 heteroatoms selected from N and O, which is optionally substituted by (C1-C6)-alkyl;
- R1 is hydrogen or (C1-C6)-alkyl;
- R2 is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n—(C3-C7)-cycloalkyl optionally substituted by (C1-C6)-alkoxy or by halogen, CH(CH3)—(C3-C7)-cycloalkyl, (CH2)n+1—C(O)—R9, (CH2)+1—CN, bicyclo[2.2.1]heptyl, (CH2)n+1—O—(C1-C6)-alkyl, (CH2)n-heterocycloalkyl, (CH2)n-aryl or (CH2)n-5 or 6-membered heteroaryl containing one, two or three heteroatoms selected from the group consisting of oxygen, sulphur or nitrogen wherein aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, halogen, (C1-C6)-alkyl and (C1-C6)-alkoxy;
- R3, R4 and R6 are each independently hydrogen, hydroxy, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or O—(C3-C6)-cycloalkyl;
- R5 is NO2, CN, C(O)R9 or SO2R10;
- R7 and R8 are each independently hydrogen or (C1-C6)-alkyl;
- R9 is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or NR7R8;
- R10 is (C1-C6)-alkyl optionally substituted by halogen, (CH2)n—(C3-C6)-cycloalkyl, (CH2)n—(C3-C6)-alkoxy, or(CH2)n-heterocycloalkyl;
- n is 0, 1, or 2;
- or a pharmaceutically acceptable acid addition salt thereof.
8 more elements
Dependencies are inferred from the claim text.