IP Library › Granted Patent US 7,371,748
Granted Patent B2
US 7,371,748 · App. 10/847,558 · Granted May 13, 2008

Benzothiazole derivatives

Assignee: Hoffman-La Roche Inc.
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Quick Facts
Patent No.
US 7,371,748
App. No.
10/847,558
Granted
May 13, 2008
Kind
B2
Abstract

This invention relates to compounds of formula I wherein R 1 and R 2 are defined herein, or a pharmaceutically acceptable salt thereof. It has been found that the compounds of formula I are adenosine receptor ligands with good affinity to the A 2A -receptor and a high selectivity to the A 1 - and A 3 receptors. These compounds are useful, inter alia, in treatment of Alzheimer's disease, depression, Parkinson's disease and ADHD.

Claims (289)

1. A compound of formula I

wherein

R 1 is selected from 1,4-dioxepanyl and tetrahydropyran-4-yl;

R 2 is selected from

—N(R)—(CH 2 ) n -5 membered non aromatic heterocycle,

—N(R)—(CH 2 ) n -5 membered non aromatic heterocycle substituted by one or two substituents selected from lower alkyl, (CH 2 ) n —OH and —NR 2 ,

—N(R)—(CH 2 ) n -6 membered non aromatic heterocycle,

—N(R)—(CH 2 ) n -6 membered non aromatic heterocycle substituted by one or two substituents selected from lower alkyl, (CH 2 ) n —OH and —NR 2 ,

—(CH 2 ) n -5 membered non aromatic heterocycle,

—(CH 2 ) n -5 membered non aromatic heterocycle substituted by one or two substituents selected from —(CH 2 ) n —OH, lower alkyl and lower alkoxy,

—(CH 2 ) n -6 membered non aromatic heterocycle,

—(CH 2 ) n -6 membered non aromatic heterocycle substituted by one or two substituents selected from —(CH 2 ) n —OH, lower alkyl and lower alkoxy

—(CH 2 ) n -5 membered aromatic heterocycle,

—(CH 2 ) n -5 membered aromatic heterocycle substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, halogen-lower alkyl, —CH 2 N(R)(CH 2 ) 2 OCH 3 , —N(R)(CH 2 ) 2 OCH 3 , —CH 2 -morpholinyl and —CH 2 -pyrrolidinyl,

—(CH 2 ) n -6 membered aromatic heterocycle,

—(CH 2 ) n -6 membered aromatic heterocycle substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, halogen-lower alkyl, —CH 2 N(R)(CH 2 ) 2 OCH 3 , —N(R)(CH 2 ) 2 OCH 3 , —CH 2 -morpholinyl and —(CH 2 ) n -pyrrolidinyl,

(CH 2 ) n -cycloalkyl,

(CH 2 ) n -cycloalkyl substituted by hydroxy,

—N(R)—(CH 2 ) n -cycloalkyl,

—N(R)—(CH 2 ) n -cycloalkyl substituted by a substituent selected from hydroxy and lower alkyl,

—N(R)—(CH 2 ) n -phenyl,

phenyl,

phenyl substituted by one or two substituents selected from the group consisting of lower alkoxy, halogen, halogen-lower alkyl, lower alkyl, —CH 2 -pyrrolidin-1-yl, —CH 2 -morpholinyl, —CH 2 N(R)(CH 2 ) 2 OCH 3 and —CH 2 —N(R)C(O)-lower alkyl,

1,4-dioxa-8-aza-spiro[4,5]decane,

2-oxa-5-aza-bicyclo[2.2.1]heptane,

1-oxa-8-aza-spiro[4,5]decane,

—N(R)—(CH 2 ) n -7-oxa-bicyclo[2.2.1]hept-2-yl, and

2-aza-bicyclo[2.2.2]decane;

R is selected from hydrogen or lower alkyl;

n is 0 or 1;

or a pharmaceutically acceptable salt thereof.

2. A compound of formula I

wherein

R 1 is 1,4-dioxepanyl;

R 2 is selected from

—N(R)—(CH 2 ) n -5 membered non aromatic heterocycle,

—N(R)—(CH 2 ) n -5 membered non aromatic heterocycle substituted by one or two substituents selected from lower alkyl, (CH 2 ) n —OH and —NR 2 ,

—N(R)—(CH 2 ) n -6 membered non aromatic heterocycle,

—N(R)—(CH 2 ) n -6 membered non aromatic heterocycle substituted by one or two substituents selected from lower alkyl, (CH 2 ) n —OH and —NR 2 ,

—(CH 2 ) n -5 membered non aromatic heterocycle,

—(CH 2 ) n -5 membered non aromatic heterocycle substituted by one or two substituents selected from —(CH 2 ) n —OH, lower alkyl and lower alkoxy,

—(CH 2 ) n -6 membered non aromatic heterocycle,

—(CH 2 ) n -6 membered non aromatic heterocycle substituted by one or two substituents selected from —(CH 2 ) n —OH, lower alkyl and lower alkoxy

—(CH 2 ) n -5 membered aromatic heterocycle,

—(CH 2 ) n -5 membered aromatic heterocycle substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, halogen-lower alkyl, —CH 2 N(R)(CH 2 ) 2 OCH 3 , —N(R)(CH 2 ) 2 OCH 3 , —CH 2 -morpholinyl and —CH 2 -pyrrolidinyl,

—(CH 2 ) n -6 membered aromatic heterocycle,

—(CH 2 ) n -6 membered aromatic heterocycle substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, halogen-lower alkyl, —CH 2 N(R)(CH 2 ) 2 OCH 3 , —N(R)(CH 2 ) 2 OCH 3 , —CH 2 -morpholinyl and —(CH 2 ) n -pyrrolidinyl,

(CH 2 ) n -cycloalkyl,

(CH 2 ) n -cycloalkyl substituted by hydroxy,

—N(R)—(CH 2 ) n -cycloalkyl,

—N(R)—(CH 2 ) n -cycloalkyl substituted by a substituent selected from hydroxy and lower alkyl,

—N(R)—(CH 2 ) n -phenyl,

phenyl,

phenyl substituted by one or two substituents selected from the group consisting of lower alkoxy, halogen, halogen-lower alkyl, lower alkyl, —CH 2 -pyrrolidin-1-yl, —CH 2 -morpholinyl, —CH 2 N(R)(CH 2 ) 2 OCH 3 and —CH 2 —N(R)C(O)-lower alkyl,

1,4-dioxa-8-aza-spiro[4,5]decane,

2-oxa-5-aza-bicyclo[2.2.1]heptane,

1-oxa-8-aza-spiro[4,5]decane,

—N(R) —(CH 2 ) n -7-oxa-bicyclo[2.2.1]hept-2-yl, and

2-aza-bicyclo[2.2.2]decane;

R is selected from hydrogen or lower alkyl; and

n is 0 or 1;

or a pharmaceutically acceptable salt thereof.

3. A compound of formula I

wherein

R 1 is 1,4-dioxepanyl;

R 2 is selected from

—N(R)—(CH 2 ) n -6 membered non aromatic heterocycle,

—N(R)—(CH 2 ) n -6 membered non aromatic heterocycle substituted by one or two substituents selected from lower alkyl and (CH 2 ) n —OH,

—(CH 2 ) n -5 membered non aromatic heterocycle,

—(CH 2 ) n -6 membered non aromatic heterocycle,

—(CH 2 ) n -6 membered non aromatic heterocycle substituted by —(CH 2 ) n —OH

—(CH 2 ) n -5 membered aromatic heterocycle substituted by one or two substituents selected from the group consisting of lower alkyl,

—(CH 2 ) n -6 membered aromatic heterocycle,

—(CH 2 ) n -6 membered aromatic heterocycle substituted by one or two substituents selected from the group consisting of lower alkoxy, halogen, —CH 2 N(R)(CH 2 ) 2 OCH 3 , and —(CH 2 ) n -pyrrolidinyl,

(CH 2 ) n -cycloalkyl,

—N(R)-cycloalkyl substituted by hydroxy,

phenyl substituted by one or two substituents selected from the group consisting of halogen, lower alkyl, —CH 2 -pyrrolidin-1-yl, —CH 2 N(R)(CH 2 ) 2 OCH 3 and —CH 2 —N(R)C(O)-lower alkyl,

1,4-dioxa-8-aza-spiro[4,5]decane,

2-oxa-5-aza-bicyclo[2.2.1]heptane, and

1-oxa-8-aza-spiro[4,5]decane;

R is selected from hydrogen or lower alkyl; and

n is 0 or 1;

or a pharmaceutically acceptable salt thereof.

4. A compound of the formula I

wherein

R 1 is tetrahydropyran-4-yl;

R 2 is selected from

—N(R)—(CH 2 ) n -5 membered non aromatic heterocycle,

—N(R)—(CH 2 ) n -5 membered non aromatic heterocycle substituted by one or two substituents selected from lower alkyl, (CH 2 ) n —OH and —NR 2 ,

—N(R)—(CH 2 ) n -6 membered non aromatic heterocycle,

—N(R)—(CH 2 ) n -6 membered non aromatic heterocycle substituted by one or two substituents selected from lower alkyl, (CH 2 ) n —OH and —NR 2 ,

—(CH 2 ) n -5 membered non aromatic heterocycle,

—(CH 2 ) n -5 membered non aromatic heterocycle substituted by one or two substituents selected from —(CH 2 ) n —OH, lower alkyl and lower alkoxy,

—(CH 2 ) n -6 membered non aromatic heterocycle,

—(CH 2 ) n -6 membered non aromatic heterocycle substituted by one or two substituents selected from —(CH 2 ) n —OH, lower alkyl and lower alkoxy

—(CH 2 ) n -5 membered aromatic heterocycle,

—(CH 2 ) n -5 membered aromatic heterocycle substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, halogen-lower alkyl, —CH 2 N(R)(CH 2 ) 2 OCH 3 , —N(R)(CH 2 ) 2 OCH 3 , —CH 2 -morpholinyl and —CH 2 -pyrrolidinyl,

—(CH 2 ) n -6 membered aromatic heterocycle,

—(CH 2 ) n -6 membered aromatic heterocycle substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, halogen-lower alkyl, —CH 2 N(R)(CH 2 ) 2 OCH 3 , —N(R)(CH 2 ) 2 OCH 3 , —CH 2 -morpholinyl and —(CH 2 ) n -pyrrolidinyl,

(CH 2 ) n -cycloalkyl,

(CH 2 ) n -cycloalkyl substituted by hydroxy,

—N(R)—(CH 2 ) n -cycloalkyl,

—N(R)—(CH 2 ) n -cycloalkyl substituted by a substituent selected from hydroxy and lower alkyl,

—N(R)—(CH 2 ) n -phenyl,

phenyl,

phenyl substituted by one or two substituents selected from the group consisting of lower alkoxy, halogen, halogen-lower alkyl, lower alkyl, —CH 2 -pyrrolidin-1-yl, —CH 2 -morpholinyl, —CH 2 N(R)(CH 2 ) 2 OCH 3 and—CH 2 —N(R)C(O)-lower alkyl,

1,4-dioxa-8-aza-spiro[4,5]decane,

2-oxa-5-aza-bicyclo[2.2.1]heptane,

1-oxa-8-aza-spiro[4,5]decane,

—N(R)—(CH 2 ) n -7-oxa-bicyclo[2.2.1]hept-2-yl, and

2-aza-bicyclo[2.2.2]decane;

R is selected from hydrogen or lower alkyl; and

n is 0 or 1;

or a pharmaceutically acceptable salt thereof.

5. A compound of formula I

wherein

R 1 is tetrahydropyran-4-yl;

R 2 is selected from

—N(R)—(CH 2 ) n -5 membered non aromatic heterocycle,

—N(R)—(CH 2 ) n -6 membered non aromatic heterocycle,

—N(R)—(CH 2 ) n -6 membered non aromatic heterocycle substituted by one or two substituents selected from lower alkyl and —NR 2 ,

—(CH 2 ) n -5 membered non aromatic heterocycle,

—(CH 2 ) n -6 membered non aromatic heterocycle,

—(CH 2 ) n -6 membered non aromatic heterocycle substituted by one or two substituents selected from —(CH 2 ) n —OH and lower alkyl,

—(CH 2 ) n -6 membered aromatic heterocycle substituted by one or two substituents selected from —CH 2 N(R)(CH 2 ) 2 OCH 3 and —CH 2 -morpholinyl,

(CH 2 ) n -cycloalkyl substituted by hydroxy,

—N(R)—(CH 2 ) n -cycloalkyl substituted by a group selected from hydroxy and lower alkyl,

—N(R)—(CH 2 ) n -phenyl,

1,4-dioxa-8-aza-spiro[4,5]decane,

2-oxa-5-aza-bicyclo[2.2.1]heptane,

—N(R)—(CH 2 ) n -7-oxa-bicyclo[2.2.1]hept-2-yl, and

2-aza-bicyclo[2.2.2]decane;

R is selected from hydrogen or lower alkyl; and

n is 0 or 1;

or a pharmaceutically acceptable salt thereof.

6. The compound of formula I in accordance with claim 3 , which is selected from

morpholine-4-carboxylic acid (7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-amide,

piperidine-1-carboxylic acid (7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-amide,

1-cyclohexyl-3-(7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-1-methyl-urea,

4-hydroxymethyl-piperidine-1-carboxylic acid (7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-amide,

3-(7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-1-methyl-1-(1-methyl-piperidin-4-yl)-urea,

1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid (7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-amide,

4-hydroxy-piperidine-1-carboxylic acid (7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl) -amide,

5-methyl-thiophene-2-carboxylic acid (7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-amide,

N-(7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-4-methoxy-benzamide, and

N-(7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-4-fluoro-benzamide.

7. The compound of formula I in accordance with claim 3 , which is selected from

cyclohexanecarboxylic acid (7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-amide,

N-(7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-2-(tetrahydro-pyran-4-yl)-acetamide,

(R)-tetrahydro-furan-2-carboxylic acid (7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-amide,

3-methyl-3H-imidazole-4-carboxylic acid (7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-amide,

N-(7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide and

N-(7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-2-methoxy-isonicotinamide.

8. The compound of formula I in accordance with claim 3 , which is selected from

trans 1-(4-hydroxy-cyclohexyl)-3-(4-methoxy-7-[1,4]dioxepan-6-yl-benzothiazol-2-yl)-1-methyl-urea,

(1S,4S)-2oxa-5-aza-bicyclo[2.2.1]heptane-5-carboxylic acid (7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-amide,

4-methoxy-piperidine-1-carboxylic acid (7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-amide,

4-chloromethyl-N-(7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-benzamide, 1-methyl-1H-pyrazole-4-carboxylic acid (7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-amide,

N-(7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-4-[(methyl-propionyl-amino)-methyl]-benzamide and

N-(7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-2-pyrrolidin-1-yl-isonicotinamide.

9. The compound of formula I in accordance with claim 5 , which is selected from

3-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-1-methyl-1-(1-methyl-piperidin-4-yl)-urea,

trans-1-(4-hydroxy-cyclohexyl)-3-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-1-methyl-urea,

cis-1-(4-hydroxy-cyclohexyl)-3-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-1-methyl-urea,

1-(4-cis-hydroxy-4-methyl-cyclohexyl)-3-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-1-methyl-urea,

3-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-1-methyl-1-(tetrahydro-pyran-4-yl)-urea,

3-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-1-methyl-1-(tetrahydro-furan-3-ylmethyl)-urea,

(rac)-(exo)-3-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-1-methyl-1-(7-oxa-bicyclo[2.2.1]hept-2-yl)-urea,

(rac)-(endo)-3-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-1-methyl-1-(7-oxa-bicyclo[2.2.1]hept-2-yl)-urea,

4-isopropyl-piperazine-1-carboxylic acid [4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-amide and

1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid [4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-amide.

10. The compound of formula I in accordance with claim 5 , which is selected from

4-hydroxy-4-methyl-piperidine-1-carboxylic acid [4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-amide,

(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]heptane-5-carboxylic acid [4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-amide,

2-aza-bicyclo[2.2.2]octane-2-carboxylic acid [4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-amide,

N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-2-(tetrahydro-pyran-4-yl)-acetamide,

N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-2-morpholin-4-ylmethyl-isonicotinamide,

2-[(2-methoxy-ethylamino)-methyl]-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide,

(trans)-2-(4-Hydroxy-cyclohexyl)-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-acetamide,

4-Hydroxymethyl-piperidine-1-carboxylic acid [4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-amide,

(exo)-(+)-3-[4-Methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-1-methyl-1-(7-oxa-bicyclo[2.2.1]hept-2-yl)-urea and

(exo)-(−)-3-[4-Methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-1-methyl-1-(7-oxa-bicyclo[2 .2.1]hept-2-yl)-urea.

11. A process for preparing a compound of formula I which comprises reacting a compound of formula

with a compound of formula

to produce a compound of formula

wherein

R 1 is selected from 1,4-dioxepanyl and tetrahydropyran-4-yl;

R 2 is selected from

—N(R)—(CH 2 ) n -5 membered non aromatic heterocycle,

—N(R)—(CH 2 ) n -5 membered non aromatic heterocycle substituted by one or two substituents selected from lower alkyl, (CH 2 ) n —OH and —NR 2 ,

—N(R)—(CH 2 ) n -6 membered non aromatic heterocycle,

—N(R)—(CH 2 ) n -6 membered non aromatic heterocycle substituted by one or two substituents selected from lower alkyl, (CH 2 ) n —OH and —NR 2 ,

—(CH 2 ) n -5 membered non aromatic heterocycle,

—(CH 2 ) n -5 membered non aromatic heterocycle substituted by one or two substituents selected from —(CH 2 ) n —OH, lower alkyl and lower alkoxy,

—(CH 2 ) n -6 membered non aromatic heterocycle,

—(CH 2 ) n -6 membered non aromatic heterocycle substituted by one or two substituents selected from —(CH 2 ) n —OH, lower alkyl and lower alkoxy

—(CH 2 ) n -5 membered aromatic heterocycle,

—(CH 2 ) n -5 membered aromatic heterocycle substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, halogen-lower alkyl, —CH 2 N(R)(CH 2 ) 2 OCH 3 , —N(R)(CH 2 ) 2 OCH 3 , —CH 2 -morpholinyl and —CH 2 -pyrrolidinyl,

—(CH 2 ) n -6 membered aromatic heterocycle,

—(CH 2 ) n -6 membered aromatic heterocycle substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, halogen-lower alkyl, —CH 2 N(R)(CH 2 ) 2 OCH 3 , —N(R)(CH 2 ) 2 OCH 3 , —CH 2 -morpholinyl and —(CH 2 ) n -pyrrolidinyl,

(CH 2 ) n -cycloalkyl,

(CH 2 ) n -cycloalkyl substituted by hydroxy,

—N(R)—(CH 2 ) n -cycloalkyl,

—N(R)—(CH 2 ) n -cycloalkyl substituted by a group selected from hydroxy and lower alkyl,

—N(R)—(CH 2 ) n -phenyl,

phenyl,

phenyl substituted by one or two substituents selected from the group consisting of lower alkoxy, halogen, halogen-lower alkyl, lower alkyl, —CH 2 -pyrrolidin-1-yl, —CH 2 -morpholinyl, —CH 2 N(R)(CH 2 ) 2 OCH 3 and —CH 2 —N(R)C(O)-lower alkyl,

1,4-dioxa-8-aza-spiro[4,5]decane,

2-oxa-5-aza-bicyclo[2.2.1]heptane,

1-oxa-8-aza-spiro[4,5]decane,

—N(R)—(CH 2 ) n -7-oxa-bicyclo[2.2.1]hept-2-yl, and

2-aza-bicyclo[2.2.2]decane;

R is selected from hydrogen or lower alkyl; and

n is 0 or 1.

12. A process for preparing a compound of formula I which comprises reacting a compound of formula

with a compound of formula

to produce a compound of formula

wherein

R 1 is selected from 1,4-dioxepanyl and tetrahydropyran-4-yl;

R 2 is selected from

—N(R)—(CH 2 ) n -5 membered non aromatic heterocycle,

—N(R)—(CH 2 ) n -5 membered non aromatic heterocycle substituted by one or two substituents selected from lower alkyl, (CH 2 ) n —OH and —NR 2 ,

—N(R)—(CH 2 ) n -6 membered non aromatic heterocycle,

—N(R)—(CH 2 ) n -6 membered non aromatic heterocycle substituted by one or two substituents selected from lower alkyl, (CH 2 ) n —OH and —NR 2 ,

—(CH 2 ) n -5 membered non aromatic heterocycle,

—(CH 2 ) n -5 membered non aromatic heterocycle substituted by one or two substituents selected from —(CH 2 ) n —OH, lower alkyl and lower alkoxy,

—(CH 2 ) n -6 membered non aromatic heterocycle,

—(CH 2 ) n -6 membered non aromatic heterocycle substituted by one or two substituents selected from —(CH 2 ) n —OH, lower alkyl and lower alkoxy

—(CH 2 ) n -5 membered aromatic heterocycle,

—(CH 2 ) n -5 membered aromatic heterocycle substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, halogen-lower alkyl, —CH 2 N(R)(CH 2 ) 2 OCH 3 , —N(R)(CH 2 ) 2 OCH 3 , —CH 2 -morpholinyl and —CH 2 -pyrrolidinyl,

—(CH 2 ) n -6 membered aromatic heterocycle,

—(CH 2 ) n -6 membered aromatic heterocycle substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, halogen-lower alkyl, —CH 2 N(R)(CH 2 ) 2 OCH 3 , —N(R)(CH 2 ) 2 OCH 3 , —CH 2 -morpholinyl and —(CH 2 ) n -pyrrolidinyl,

(CH 2 ) n -cycloalkyl,

(CH 2 ) n -cycloalkyl substituted by hydroxy,

—N(R)—(CH 2 ) n -cycloalkyl,

—N(R)—(CH 2 ) n -cycloalkyl substituted by a group selected from hydroxy and lower alkyl,

—N(R)—(CH 2 ) n -phenyl,

phenyl,

phenyl substituted by one or two substituents selected from the group consisting of lower alkoxy, halogen, halogen-lower alkyl, lower alkyl, —CH 2 -pyrrolidin-1-yl, —CH 2 -morpholinyl, —CH 2 N(R)(CH 2 ) 2 OCH 3 and —CH 2 —N(R)C(O)-lower alkyl,

1,4-dioxa-8-aza-spiro[4,5]decane,

2-oxa-5-aza-bicyclo[2.2.1]heptane,

1-oxa-8-aza-spiro[4,5]decane,

—N(R)—(CH 2 ) n -7-oxa-bicyclo[2.2.1]hept-2-yl, and

2-aza-bicyclo[2.2.2]decane;

L is a leaving group selected from the group consisting of halogen, —O-phenyl and O-lower alkyl,

R 3 is selected from

—(CH 2 ) n -5 membered non aromatic heterocycle,

—(CH 2 ) n -5 membered non aromatic heterocycle substituted by one or two substituents selected from the group consisting of lower alkyl or —NR 2 ,

—(CH 2 ) n -6 membered non aromatic heterocycle,

—(CH 2 ) n - or 6 membered non aromatic heterocycle substituted by one or two substituents selected from the group consisting of lower alkyl or —NR 2 , cycloalkyl,

cycloalkyl substituted by a substituent selected from hydroxy and lower alkyl and

7-oxa-bicyclo[2.2.1]hept-2-yl;

R is selected from hydrogen or lower alkyl; and

n is 0 or 1.

13. The process of claim 11 , which further comprises converting the compounds obtained into a pharmaceutically acceptable salt.

14. The process of claim 12 , which further comprises converting the compounds obtained into a pharmaceutically acceptable salt.

15. A pharmaceutical composition which comprises a compound of formula I

wherein

R 1 is selected from 1,4-dioxepanyl and tetrahydropyran-4-yl;

R 2 is selected from

—N(R)—(CH 2 ) n -5 membered non aromatic heterocycle,

—N(R)—(CH 2 ) n -5 membered non aromatic heterocycle substituted by one or two substituents selected from lower alkyl, (CH 2 ) n —OH and —NR 2 ,

—N(R)—(CH 2 ) n -6 membered non aromatic heterocycle,

—N(R)—(CH 2 ) n -6 membered non aromatic heterocycle substituted by one or two substituents selected from lower alkyl, (CH 2 ) n —OH and —NR 2 ,

—(CH 2 ) n -5 membered non aromatic heterocycle,

—(CH 2 ) n -6 membered non aromatic heterocycle substituted by one or two substituents selected from —(CH 2 ) n —OH, lower alkyl and lower alkoxy,

—(CH 2 ) n -6 membered non aromatic heterocycle,

—(CH 2 ) n -6 membered non aromatic heterocycle substituted by one or two substituents selected from —(CH 2 ) n —OH, lower alkyl and lower alkoxy

—(CH 2 ) n -5 membered aromatic heterocycle,

—(CH 2 ) n -5 membered aromatic heterocycle substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, halogen-lower alkyl, —CH 2 N(R)(CH 2 ) 2 OCH 3 , —N(R)(CH 2 ) 2 OCH 3 , —CH 2 -morpholinyl and —CH 2 -pyrrolidinyl,

—(CH 2 ) n -6 membered aromatic heterocycle,

—(CH 2 ) n -6 membered aromatic heterocycle substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, halogen-lower alkyl, —CH 2 N(R)(CH 2 ) 2 OCH 3 , —N(R)(CH 2 ) 2 OCH 3 , —CH 2 -morpholinyl and —(CH 2 ) n -pyrrolidinyl,

(CH 2 ) n -cycloalkyl,

(CH 2 ) n -cycloalkyl substituted by hydroxy,

—N(R)—(CH 2 ) n -cycloalkyl,

—N(R)—(CH 2 ) n -cycloalkyl substituted by a group selected from hydroxy and lower alkyl,

—N(R)—(CH 2 ) n -phenyl,

phenyl,

phenyl substituted by one or two substituents selected from the group consisting of lower alkoxy, halogen, halogen-lower alkyl, lower alkyl, —CH 2 -pyrrolidin-1-yl, —CH 2 -morpholinyl, —CH 2 N(R)(CH 2 ) 2 OCH 3 and —CH 2 —N(R)C(O)-lower alkyl,

1,4-dioxa-8-aza-spiro[4,5]decane,

2-oxa-5-aza-bicyclo[2.2.1]heptane,

1-oxa-8-aza-spiro[4,5]decane,

—N(R)—(CH 2 ) n -7-oxa-bicyclo[2.2.1]hept-2-yl, and

2-aza-bicyclo[2.2.2]decane;

R is selected from hydrogen or lower alkyl; and

n is 0 or 1;

or a pharmaceutically acceptable salt thereof,

and a pharmaceutically acceptable carrier.

16. A compound according to claim 1 in which R 1 is tetrahydropyran-4-yl and R 2 is —N(R)—(CH 2 ) n -7-oxa-bicyclo[2.2.1]hept-2-yl.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 28, 2005
From: F. HOFFMANN-LA ROCHE AG
To: HOFFMANN-LA ROCHE INC.
Reel/Frame 016426/0662 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 28, 2005
From: FLOHR, ALEXANDER; JAKOB-ROETNE, ROLAND; NORCROSS, ROGER DAVID; RIEMER, CLAUS
To: F. HOFFMANN-LA ROCHE AG
Reel/Frame 016428/0379 →
Priority Claims (1)
EP 03011039 · May 19, 2003 · regional
Continuity (1)
Related Publication 20040235915A1 · Nov 25, 2004