3-substituted 6,7-dihydroxytetrahydroisoquinoline derivatives for use as antibacterial agents

1. A compound of formula 1

wherein

R 1 represents hydrogen or lower alkyl,

R 2 represents hydrogen; aryl; aryl-lower alkyl; heteroaryl; or heteroaryl-lower alkyl;

wherein the aryl and heteroaryl residues may be mono-, di- or tri-substituted with lower alkyl, hydroxy, lower alkoxy, halogen, trifluoromethyl, amino, lower alkylamino, or lower alkylendioxy, and which substituents may be the same or different,

R 3 represents one of the groups: —(CH 2 ) m —O—(CH 2 )n-Ar 1 ; —(CH 2 ) m —NH—(CH 2 ) n —Ar 1 ; —(CH 2 ) m —S—(CH 2 ) n —Ar 1 ; —(CH═CH)—(CH 2 ) n —Ar 1 ; —CHOH—(CH 2 ) n —Ar 1 ; —(CH 2 ) n —Ar 2 ; —CH 2 —Ar 2′ ; —(CH 2 )n-Ar 3 ; and —(CH 2 ) n —Ar 4 , wherein

m represents the number 1, 2 or 3;

n represents the number 0, 1, 2 or 3; and

in case Ar 2 is present, n has the meaning 0, 2 or 3;

Ar 1 represents hydrogen; an aryl or heteroaryl group, which group may be unsubstituted or mono-, di-, or trisubstituted with a substituent independently selected from the group D, wherein D represents hydroxy, lower alkyl, lower alkoxy, lower alkylendioxy, aryl, aryloxy, lower alkyl-sulfanyl, arylsulfanyl, halogen, amino, lower alkylamino, lower di-alkylamino, or trifluoromethyl;

Ar 2 represents an aryl or heteroaryl group, which group is di-, or trisubstituted with a substituent selected from the group D, wherein D is as defined above;

Ar 2′ represents an aryl or heteroaryl group, which group is di-, or trisubstituted with, lower alkyl, lower alkylendioxy, aryl, aryloxy, lower alkyl-sulfanyl, arylsulfanyl, halogen, amino, lower alkylamino, lower di-alkylamino, or trifluoromethyl;

Ar 3 represents an aryl or heteroaryl group, which group is monosubstituted with aryl, aryloxy, arylsulfanyl, lower alkyl-sulfanyl, trifluoromethyl, or lower alkylendioxy;

Ar 4 represents an aryl or heteroaryl group, which group is monosubstituted with Ar 1 with the proviso that Ar 1 does not represent hydrogen, or a pure enantiomer, a mixture of enantiomers, a pure diastereomer, a mixture of diastereomers, diastereomeric racemates and stereoisomers, or a pharmaceutically acceptable salt thereof.

2. A compound of formula 2

wherein

R 1 represents hydrogen or lower alkyl, and

R 3 represents one of the groups: —(CH 2 ) m —O—(CH 2 )n—Ar 1 ; —(CH 2 ) m —NH—(CH 2 ) n —Ar 1 ; —(CH 2 ) m —S—(CH 2 ) n —Ar 1 ; —(CH═CH)—(CH 2 ) n —Ar 1 ; —CHOH—(CH 2 ) n —Ar 1 ; —(CH 2 ) n —Ar 2 ; —CH 2 —Ar 2′ ; —(CH 2 ) n —Ar 3 ; and —(CH 2 ) n —Ar 4 ,

wherein

m represents the number 1, 2 or 3;

n represents the number 0, 1, 2 or 3; and

in case Ar 2 is present, n has the meaning 0, 2 or 3;

Ar 1 represents hydrogen; an aryl or heteroaryl group, which group may be unsubstituted or mono-, di-, or trisubstituted with a substituent independently selected from the group D, wherein D represents hydroxy, lower alkyl, lower alkoxy, lower alkylendioxy, aryl, aryloxy, lower alkyl-sulfanyl, arylsulfanyl, halogen, amino, lower alkylamino, lower di-alkylamino, or trifluoromethyl;

Ar 2 represents an aryl or heteroaryl group, which group is di-, or trisubstituted with a substituent selected from the group D, wherein D is as defined above;

Ar 2 ′ represents an aryl or heteroaryl group, which group is di-, or trisubstituted with, lower alkyl, lower alkylendioxy, aryl, aryloxy, lower alkyl-sulfanyl, arylsulfanyl, halogen, amino, lower alkylamino, lower di-alkylamino, or trifluoromethyl;

Ar 3 represents an aryl or heteroaryl group, which group is monosubstituted with aryl, aryloxy, arylsulfanyl, lower alkyl-sulfanyl, trifluoromethyl, or lower alkylendioxy;

Ar 4 represents an aryl or heteroaryl group, which group is monosubstituted with Ar 1 with the proviso that Ar 1 does not represent hydrogen, or a pure enantiomer, a mixture of enantiomers, a pure diastereomer, a mixture of diastereomers, diastereomeric racemates and stereoisomers, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein R 1 represents hydrogen.

4. A compound selected from the group consisting of:

3-(4-Phenoxy-phenyl)-1,2,3,4-tetrahydro-isoquinoline-6,7-diol;

2-Benzyl-3-(4-phenoxy-phenyl)-1,2,3,4-tetrahydro-isoquinoline-6,7-diol;

1-Methyl-3-(4-phenoxy-phenyl)-1,2,3,4-tetrahydro-isoquinoline-6,7-diol;

3-(4-Methoxy-naphthalen-1-yl)-1,2,3,4-tetrahydro-isoquinoline-6,7-diol;

3-(4-Hydroxy-naphthalen-1-yl)-1,2,3,4-tetrahydro-isoquinoline-6,7-diol;

3-Hydroxymethyl-1,2,3,4-tetrahydro-isoquinoline-6,7-diol;

3-Dibenzofuran-2-yl-1,2,3,4-tetrahydro-isoquinoline-6,7-diol;

3-(4-Phenylsulfanyl-phenyl)-1,2,3,4-tetrahydro-isoquinoline-6,7-diol;

3-(2,4-Dichloro-phenyl)-1,2,3,4-tetrahydro-isoquinoline-6,7-diol;

3-(2,4-Dichloro-phenoxymethyl)-1,2,3,4-tetrahydro-isoquinoline-6,7-diol;

2-Benzyl-3-(2,4-dichloro-phenoxymethyl)-1,2,3,4-tetrahydro-isoquinoline-6,7-diol;

3-Biphenyl-4-yl-1,2,3,4-tetrahydro-isoquinoline-6,7-diol;

3-(3,4-Dichloro-phenoxymethyl)-1,2,3,4-tetrahydro-isoquinoline-6,7-diol;

3-(2,5-Dichloro-phenoxymethyl)-1,2,3,4-tetrahydro-isoquinoline-6,7-diol;

3-(4-Chloro-phenyl)-1,2,3,4-tetrahydro-isoquinoline-6,7-diol;

3-(4-Bromo-phenyl)-1, 2,3,4-tetrahydro-isoquinoline-6,7-diol;

3-(4′-Trifluoromethyl-biphenyl-4-yl)-1,2,3,4-tetrahydro-isoquinoline-6,7-diol;

3-(4′-Dimethylamino-biphenyl-4-yl)-1,2,3,4-tetrahydro-isoquinoline-6,7-diol;

3-(4′-Hydroxy-biphenyl-4-yl)-1,2,3,4-tetrahydro-isoquinoline-6,7-diol;

3-(2′-Hydroxy-biphenyl-4-yl)-1,2,3,4-tetrahydro-isoquinoline-6,7-diol;

3-(2′,4′-Difluoro-biphenyl-4-yl)-1,2,3,4-tetrahydro-isoquinoline-6,7-diol; and

4′-(6,7-Dihydroxy-1,2,3,4-tetrahydro-isoquinolin-3-yl)-biphenyl-3-carbonitrile.

5. A pharmaceutical composition comprising a compound of any one of claims 1 - 3 or 4 and a pharmaceutically acceptable carrier and/or an adjuvant.

6. A process for the manufacture of a pharmaceutical composition, comprising one or more compounds as claimed in any one of claims 1 - 3 or 4 as active ingredients, which process comprises mixing one or more active ingredients with a pharmaceutically acceptable excipient.

7. A method of treating a bacterial infection, comprising administering a therapeutically effective amount of the compound of any one of claims 1 - 3 or 4 .

8. The method of claim 7 , wherein the infection is caused by a Gram positive pathogen and/or a Gram negative pathogen.

9. A method of treating a bacterial infection, comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 5 .

10. The method of claim 9 , wherein the infection is caused by a Gram positive pathogen and/or a Gram negative pathogen.