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US 2009/0023704 A1Published application
Novel Compounds 737
AssigneeAstraZeneca AB
InventorsLeifeng Cheng, Sara Holmqvist, Florian Raubacher, Peter Schell
Life of this patent
Estimating the term…
Abstract
The present invention relates to novel xanthine compounds of the general formula (I) wherein R1, R2, R3 and R4 are as defined, having a positive allosteric GABAB receptor (GBR) modulator effect, methods for the preparation of said compounds and to their use, optionally in combination with a GABAB agonist, for the inhibition of transient lower esophageal sphincter relaxations, for the treatment of gastroesophageal reflux disease, as well as for the treatment of functional gastrointestinal disorders and irritable bowel syndrome (IBS).
Claims15
A compound of the general formula (I)
- or a pharmaceutically acceptable salt thereof;
- wherein
- R1 is selected from halogen;
- C1-C10 alkyl;
- C1-C10 alkoxy;
- hydroxy-C1-C10 alkyl;
- C1-C10 alkoxy-C1-C10 alkyl;
- C3-C10 cycloalkyl;
- amino substituted by one or more of C1-C10 alkyl and C1-C10 alkoxy-C1-C10 alkyl;
- and heterocyclyl unsubstituted or substituted by one or more of C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkoxy-C1-C10 alkyl, di-C1-C10 alkylamino, oxo and heterocyclyl-C1-C10 alkyl;
- R2 is selected from benzyl substituted by one or more of halogen;
- cyano;
- C1-C10 alkyl;
- C1-C10 alkoxy;
- aroyl;
- halo-C1-C10 alkyl;
- aryl-C1-C10 alkoxy and C1-C10 alkoxycarbonyl;
- 2-naphthylmethyl;
- 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-ylmethyl;
- 2-(4-chlorophenyl)ethyl;
- 2,1,3-benzothiadiazol-5-ylmethyl;
- and 1-[5-(trifluoromethyl)]-1,3-benzothiazol-2-ylmethyl;
- R3 is selected from C1-C10 alkyl and aryl substituted by one or more of halogen;
- R4 is selected from ethyl;
- isobutyl;
- propyl;
- 3,3-dimethylbutyl;
- C1-C10 alkyl substituted by one or more of hydroxy, oxo, C1-C10 alkoxy, C1-C10 alkoxycarbonylamino, tri-C1-C10 alkylsilyl, tri-C1-C10 alkylsilyloxy, C1-C10 alkylsulfonyl and aryloxy, wherein the aryloxy is substituted by one or more of halo-C1-C10 alkyl;
- amino-C1-C10 alkyl substituted by oxo;
- di-C1-C10 alkylamino-C1-C10 alkyl unsubstituted or substituted by one or more of oxo;
- halo-C1-C10 alkyl unsubstituted or substituted by one or more of hydroxy;
- C1-C10 alkoxycarbonyl-C1-C10 alkyl;
- C2-C10 alkenyl;
- C3-C10 cycloalkyl-C1-C10 alkyl unsubstituted or substituted by oxo;
- aryl-C1-C10 alkyl unsubstituted or substituted by one or more of halogen, C1-C10 alkoxy, halo-C1-C10 alkyl, halo-C1-C10 alkoxy, halo-C1-C10 alkylthio, C1-C10 alkylsulfonyl, oxo and heteroaryl;
- heteroaryl-C1-C10 alkyl unsubstituted or substituted by one or more of halogen, C1-C10 alkyl, C1-C10 alkylsulfonyl, halo-C1-C10 alkyl, oxo and aryl, wherein the aryl group is unsubstituted or substituted by halogen;
- heterocyclyl-C1-C10 alkyl unsubstituted or substituted by one or more of halogen, oxo and aryl;
- with the proviso that the compound is not:
- 1-benzyl-3-isobutylxanthine;
- 1-benzyl-3-butylxanthine;
- 1-(4-chlorobenzyl)-3-ethyl-8-isopropylxanthine;
- 1,3-dibenzylxanthine;
- and
- 1,3-di-(4-chlorobenzyl)-8-isopropylxanthine.
41 more elements
4-5. (canceled)
7-15. (canceled)
A method of treating gastroesophageal reflux disease (GERD) comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, optionally in combination with a GABAB receptor agonist, to a subject, wherein the compound of formula (I) comprises
- wherein
- R1 is selected from halogen;
- C1-C10 alkyl;
- C1-C10 alkoxy;
- hydroxy-C1-C10 alkyl;
- C1-C10 alkoxy-C1-C10 alkyl;
- C3-C10 cycloalkyl;
- amino substituted by one or more of C1-C10 alkyl and C1-C10 alkoxy-C1-C10 alkyl;
- and heterocyclyl unsubstituted or substituted by one or more of C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkoxy-C1-C10 alkyl, di-C1-C10 alkylamino, oxo and heterocyclyl-C1-C10 alkyl;
- R2 is selected from benzyl substituted by one or more of halogen;
- cyano;
- C1-C10 alkyl;
- C1-C10 alkoxy;
- aroyl;
- halo-C1-C10 alkyl;
- aryl-C1-C10 alkoxy and C1-C10 alkoxycarbonyl;
- 2-naphthylmethyl;
- 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-ylmethyl;
- 2-(4-chlorophenyl)ethyl;
- 2,1,3-benzothiadiazol-5-ylmethyl;
- and 1-[5-(trifluoromethyl)]-1,3-benzothiazol-2-ylmethyl;
- R3 is selected from C1-C10 alkyl and aryl substituted by one or more of halogen;
- and
- R4 is selected from ethyl;
- isobutyl;
- propyl;
- 3,3-dimethylbutyl;
- C1-C10 alkyl substituted by one or more of hydroxy, oxo, C1-C10 alkoxy, C1-C10 alkoxycarbonylamino, tri-C1-C10 alkylsilyl, tri-C1-C10 alkylsilyloxy, C1-C10 alkylsulfonyl and aryloxy, wherein the aryloxy is substituted by one or more of halo-C1-C10 alkyl;
- amino-C1-C10 alkyl substituted by oxo;
- di-C1-C10 alkylamino-C1-C10 alkyl unsubstituted or substituted by one or more of oxo;
- halo-C1-C10 alkyl unsubstituted or substituted by one or more of hydroxy;
- C1-C10 alkoxycarbonyl-C1-C10 alkyl;
- C2-C10 alkenyl;
- C3-C10 cycloalkyl-C1-C10 alkyl unsubstituted or substituted by oxo;
- aryl-C1-C10 alkyl unsubstituted or substituted by one or more of halogen, C1-C10 alkoxy, halo-C1-C10 alkyl, halo-C1-C10 alkoxy, halo-C1-C10 alkylthio, C1-C10 alkylsulfonyl, oxo and heteroaryl;
- heteroaryl-C1-C10 alkyl unsubstituted or substituted by one or more of halogen, C1-C10 alkyl, C1-C10 alkylsulfonyl, halo-C1-C10 alkyl, oxo and aryl, wherein the aryl group is unsubstituted or substituted by halogen;
- heterocyclyl-C1-C10 alkyl unsubstituted or substituted by one or more of halogen, oxo and aryl.
34 more elements
A method for the prevention of reflux comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, optionally in combination with a GABAB receptor agonist, to a subject, wherein the compound of formula (I) comprises
- wherein
- R1 is selected from halogen;
- C1-C10 alkyl;
- C1-C10 alkoxy;
- hydroxy-C1-C10 alkyl;
- C1-C10 alkoxy-C1-C10 alkyl;
- C3-C10 cycloalkyl;
- amino substituted by one or more of C1-C10 alkyl and C1-C10 alkoxy-C1-C10 alkyl;
- and heterocyclyl unsubstituted or substituted by one or more of C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkoxy-C1-C10 alkyl, di-C1-C10 alkylamino, oxo and heterocyclyl-C1-C10 alkyl;
- R2 is selected from benzyl substituted by one or more of halogen;
- cyano;
- C1-C10 alkyl;
- C1-C10 alkoxy;
- aroyl;
- halo-C1-C10 alkyl;
- aryl-C1-C10 alkoxy and C1-C10 alkoxycarbonyl;
- 2-naphthylmethyl;
- 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-ylmethyl;
- 2-(4-chlorophenyl)ethyl;
- 2,1,3-benzothiadiazol-5-ylmethyl;
- and 1-[5-(trifluoromethyl)]-1,3-benzothiazol-2-ylmethyl;
- R3 is selected from C1-C10 alkyl and aryl substituted by one or more of halogen;
- and
- R4 is selected from ethyl;
- isobutyl;
- propyl;
- 3,3-dimethylbutyl;
- C1-C10 alkyl substituted by one or more of hydroxy, oxo, C1-C10 alkoxy, C1-C10 alkoxycarbonylamino, tri-C1-C10 alkylsilyl, tri-C1-C10 alkylsilyloxy, C1-C10 alkylsulfonyl and aryloxy, wherein the aryloxy is substituted by one or more of halo-C1-C10 alkyl;
- amino-C1-C10 alkyl substituted by oxo;
- di-C1-C10 alkylamino-C1-C10 alkyl unsubstituted or substituted by one or more of oxo;
- halo-C1-C10 alkyl unsubstituted or substituted by one or more of hydroxy;
- C1-C10 alkoxycarbonyl-C1-C10 alkyl;
- C2-C10 alkenyl;
- C3-C10 cycloalkyl-C1-C10 alkyl unsubstituted or substituted by oxo;
- aryl-C1-C10 alkyl unsubstituted or substituted by one or more of halogen, C1-C10 alkoxy, halo-C1-C10 alkyl, halo-C1-C10 alkoxy, halo-C1-C10 alkylthio, C1-C10 alkylsulfonyl, oxo and heteroaryl;
- heteroaryl-C1-C10 alkyl unsubstituted or substituted by one or more of halogen, C1-C10 alkyl, C1-C10 alkylsulfonyl, halo-C1-C10 alkyl, oxo and aryl, wherein the aryl group is unsubstituted or substituted by halogen;
- heterocyclyl-C1-C10 alkyl unsubstituted or substituted by one or more of halogen, oxo and aryl.
34 more elements
A method for the inhibition of transient lower esophageal sphincter relaxations (TLESRs) comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, optionally in combination with a GABAB receptor agonist, to a subject, wherein the compound of formula (I) comprises
- wherein
- R1 is selected from halogen;
- C1-C10 alkyl;
- C1-C10 alkoxy;
- hydroxy-C1-C10 alkyl;
- C1-C10 alkoxy-C1-C10 alkyl;
- C3-C10 cycloalkyl;
- amino substituted by one or more of C1-C10 alkyl and C1-C10 alkoxy-C1-C10 alkyl;
- and heterocyclyl unsubstituted or substituted by one or more of C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkoxy-C1-C10 alkyl, di-C1-C10 alkylamino, oxo and heterocyclyl-C1-C10 alkyl;
- R2 is selected from benzyl substituted by one or more of halogen;
- cyano;
- C1-C10 alkyl;
- C1-C10 alkoxy;
- aroyl;
- halo-C1-C10 alkyl;
- aryl-C1-C10 alkoxy and C1-C10 alkoxycarbonyl;
- 2-naphthylmethyl;
- 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-ylmethyl;
- 2-(4-chlorophenyl)ethyl;
- 2,1,3-benzothiadiazol-5-ylmethyl;
- and 1-[5-(trifluoromethyl)]-1,3-benzothiazol-2-ylmethyl;
- R3 is selected from C1-C10 alkyl and aryl substituted by one or more of halogen;
- and
- R4 is selected from ethyl;
- isobutyl;
- propyl;
- 3,3-dimethylbutyl;
- C1-C10 alkyl substituted by one or more of hydroxy, oxo, C1-C10 alkoxy, C1-C10 alkoxycarbonylamino, tri-C1-C10 alkylsilyl, tri-C1-C10 alkylsilyloxy, C1-C10 alkylsulfonyl and aryloxy, wherein the aryloxy is substituted by one or more of halo-C1-C10 alkyl;
- amino-C1-C10 alkyl substituted by oxo;
- di-C1-C10 alkylamino-C1-C10 alkyl unsubstituted or substituted by one or more of oxo;
- halo-C1-C10 alkyl unsubstituted or substituted by one or more of hydroxy;
- C1-C10 alkoxycarbonyl-C1-C10 alkyl;
- C2-C10 alkenyl;
- C3-C10 cycloalkyl-C1-C10 alkyl unsubstituted or substituted by oxo;
- aryl-C1-C10 alkyl unsubstituted or substituted by one or more of halogen, C1-C10 alkoxy, halo-C1-C10 alkyl, halo-C1-C10 alkoxy, halo-C1-C10 alkylthio, C1-C10 alkylsulfonyl, oxo and heteroaryl;
- heteroaryl-C1-C10 alkyl unsubstituted or substituted by one or more of halogen, C1-C10 alkyl, C1-C10 alkylsulfonyl, halo-C1-C10 alkyl, oxo and aryl, wherein the aryl group is unsubstituted or substituted by halogen;
- heterocyclyl-C1-C10 alkyl unsubstituted or substituted by one or more of halogen, oxo and aryl.
34 more elements
A method for the treatment of a functional gastrointestinal disorder comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, optionally in combination with a GABAB receptor agonist, to a subject, wherein the compound of formula (I) comprises
- wherein
- R1 is selected from halogen;
- C1-C10 alkyl;
- C1-C10 alkoxy;
- hydroxy-C1-C10 alkyl;
- C1-C10 alkoxy-C1-C10 alkyl;
- C3-C10 cycloalkyl;
- amino substituted by one or more of C1-C10 alkyl and
- C1-C10 alkoxy-C1-C10 alkyl;
- and heterocyclyl unsubstituted or substituted by one or more of C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkoxy-C1-C10 alkyl, di-C1-C10 alkylamino, oxo and heterocyclyl-C1-C10 alkyl;
- R2 is selected from benzyl substituted by one or more of halogen;
- cyano;
- C1-C10 alkyl;
- C1-C10 alkoxy;
- aroyl;
- halo-C1-C10 alkyl;
- aryl-C1-C10 alkoxy and C1-C10 alkoxycarbonyl;
- 2-naphthylmethyl;
- 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-ylmethyl;
- 2-(4-chlorophenyl)ethyl;
- 2,1,3-benzothiadiazol-5-ylmethyl;
- and 1-[5-(trifluoromethyl)]-1,3-benzothiazol-2-ylmethyl;
- R3 is selected from C1-C10 alkyl and aryl substituted by one or more of halogen;
- and
- R4 is selected from ethyl;
- isobutyl;
- propyl;
- 3,3-dimethylbutyl;
- C1-C10 alkyl substituted by one or more of hydroxy, oxo, C1-C10 alkoxy, C1-C10 alkoxycarbonylamino, tri-C1-C10 alkylsilyl, tri-C1-C10 alkylsilyloxy, C1-C10 alkylsulfonyl and aryloxy, wherein the aryloxy is substituted by one or more of halo-C1-C10 alkyl;
- amino-C1-C10 alkyl substituted by oxo;
- di-C1-C10 alkylamino-C1-C10 alkyl unsubstituted or substituted by one or more of oxo;
- halo-C1-C10 alkyl unsubstituted or substituted by one or more of hydroxy;
- C1-C10 alkoxycarbonyl-C1-C10 alkyl;
- C2-C10 alkenyl;
- C3-C10 cycloalkyl-C1-C10 alkyl unsubstituted or substituted by oxo;
- aryl-C1-C10 alkyl unsubstituted or substituted by one or more of halogen, C1-C10 alkoxy, halo-C1-C10 alkyl, halo-C1-C10 alkoxy, halo-C1-C10 alkylthio, C1-C10 alkylsulfonyl, oxo and heteroaryl;
- heteroaryl-C1-C10 alkyl unsubstituted or substituted by one or more of halogen, C1-C10 alkyl, C1-C10 alkylsulfonyl, halo-C1-C10 alkyl, oxo and aryl, wherein the aryl group is unsubstituted or substituted by halogen;
- heterocyclyl-C1-C10 alkyl unsubstituted or substituted by one or more of halogen, oxo and aryl.
35 more elements
A method for the treatment of irritable bowel syndrome (IBS) comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, optionally in combination with a GABAB receptor agonist, to a subject, wherein the compound of formula (I) comprises
- wherein
- R1 is selected from halogen;
- C1-C10 alkyl;
- C1-C10 alkoxy;
- hydroxy-C1-C10 alkyl;
- C1-C10 alkoxy-C1-C10 alkyl;
- C3-C10 cycloalkyl;
- amino substituted by one or more of C1-C10 alkyl and C1-C10 alkoxy-C1-C10 alkyl;
- and heterocyclyl unsubstituted or substituted by one or more of C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkoxy-C1-C10 alkyl, di-C1-C10 alkylamino, oxo and heterocyclyl-C1-C10 alkyl;
- R2 is selected from benzyl substituted by one or more of halogen;
- cyano;
- C1-C10 alkyl;
- C1-C10 alkoxy;
- aroyl;
- halo-C1-C10 alkyl;
- aryl-C1-C10 alkoxy and C1-C10 alkoxycarbonyl;
- 2-naphthylmethyl;
- 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-ylmethyl;
- 2-(4-chlorophenyl)ethyl;
- 2,1,3-benzothiadiazol-5-ylmethyl;
- and 1-[5-(trifluoromethyl)]-1,3-benzothiazol-2-ylmethyl;
- R3 is selected from C1-C10 alkyl and aryl substituted by one or more of halogen;
- and
- R4 is selected from ethyl;
- isobutyl;
- propyl;
- 3,3-dimethylbutyl;
- C1-C10 alkyl substituted by one or more of hydroxy, oxo, C1-C10 alkoxy, C1-C10 alkoxycarbonylamino, tri-C1-C10 alkylsilyl, tri-C1-C10 alkylsilyloxy, C1-C10 alkylsulfonyl and aryloxy, wherein the aryloxy is substituted by one or more of halo-C1-C10 alkyl;
- amino-C1-C10 alkyl substituted by oxo;
- di-C1-C10 alkylamino-C1-C10 alkyl unsubstituted or substituted by one or more of oxo;
- halo-C1-C10 alkyl unsubstituted or substituted by one or more of hydroxy;
- C1-C10 alkoxycarbonyl-C1-C10 alkyl;
- C2-C10 alkenyl;
- C3-C10 cycloalkyl-C1-C10 alkyl unsubstituted or substituted by oxo;
- aryl-C1-C10 alkyl unsubstituted or substituted by one or more of halogen, C1-C10 alkoxy, halo-C1-C10 alkyl, halo-C1-C10 alkoxy, halo-C1-C10 alkylthio, C1-C10 alkylsulfonyl, oxo and heteroaryl;
- heteroaryl-C1-C10 alkyl unsubstituted or substituted by one or more of halogen, C1-C10 alkyl, C1-C10 alkylsulfonyl, halo-C1-C10 alkyl, oxo and aryl, wherein the aryl group is unsubstituted or substituted by halogen;
- heterocyclyl-C1-C10 alkyl unsubstituted or substituted by one or more of halogen, oxo and aryl.
34 more elements
Dependencies are inferred from the claim text.