Benzofuran derivatives and their use in the treatment of microbial infections
The invention relates to new benzofuran derivatives and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as anti-infectives.
1. A compound of formula I
wherein
R 1 represents the groups
whereby in these groups R 5 is hydrogen, lower alkyl with 1 to 4 carbon atoms, or the group
wherein
R 8 represents lower alkyloxy, lower alkylamino, or lower alkyl with 1 to 4 carbon atoms;
R 9 represents lower alkyl with 1 to 4 carbon atoms;
R 8 and R 9 together form a 5- or 6-membered heterocyclic ring containing one to two hetero atoms which can be the same or different and are oxygen or nitrogen;
R 6 represents hydrogen, halogen, nitro, or lower alkyloxy;
R 7 represents hydrogen;
R 2 and R 3 independently represent hydrogen, lower alkyl with 1 to 3 carbon atoms, or together a lower alkylene group with 1 to 3 carbon atoms bridging the oxygen atoms and forming a five, six or seven membered ring;
R 4 represents hydrogen;
or a pharmaceutically acceptable salt thereof.
2. A compound of formula I′
wherein
R 1 represents the groups
whereby in these groups R 5 is hydrogen, lower alkyl with 1 to 4 carbon atoms, or the group
wherein
R 8 represents lower alkyloxy, or lower alkyl with 1 to 4 carbon atoms;
R 9 represents, lower alkyl with 1 to 4 carbon atoms;
R 8 and R 9 together form a 5- or 6-membered heterocyclic ring containing one to two hetero atoms which can be the same or different and are oxygen or nitrogen;
R 6 represents hydrogen, halogen, nitro, or lower alkyloxy;
R 7 represents hydrogen;
R 2 and R 3 independently represent hydrogen, lower alkyl with 1 to 3 carbon atoms, or together a lower alkylene group with 1 to 3 carbon atoms bridging the oxygen atoms and forming a five, six or seven membered ring;
R 4 represents hydrogen;
or a pharmaceutically acceptable salt thereof.
3. A compound of formula II
wherein
R 2 and R 3 represent methyl;
R 4 represents hydrogen;
R 5 is hydrogen, lower alkyl with 1 to 4 carbon atoms, or the group
wherein
R 8 represents lower alkyloxy, lower alkylamino, or lower alkyl with 1 to 4 carbon atoms;
R 9 represents lower alkyl with 1 to 4 carbon atoms;
R 8 and R 9 together form a 5- or 6-membered heterocylic ring containing one to two hetero atoms which can be the same or different and are oxygen or nitrogen;
R 6 represents hydrogen, halogen, nitro, or lower alkyloxy;
R 7 represents hydrogen;
or a pharmaceutically acceptable salt thereof.
4. A compound of formula III
wherein
R 2 and R 3 represent methyl;
R 4 represents hydrogen;
R 5 is hydrogen, lower alkyl with 1 to 4 carbon atoms, or the group
wherein
R 8 represents lower alkyloxy, lower alkylamino, or lower alkyl with 1 to 4 carbon atoms;
R 9 represents lower alkyl with 1 to 4 carbon atoms;
R 8 and R 9 together form a 5- or 6-membered heterocylic ring containing one to two hetero atoms which can be the same or different and are oxygen or nitrogen;
R 6 represents hydrogen, halogen, nitro, or lower alkyloxy;
R 7 represents hydrogen;
or a pharmaceutically acceptable salt thereof.
5. A compound of formula IV
wherein
R 2 and R 3 represent methyl;
R 4 represents hydrogen;
R 5 is hydrogen, lower alkyl with 1 to 4 carbon atoms, or the group
wherein
R 8 represents lower alkyloxy, lower alkylamino, or lower alkyl with 1 to 4 carbon atoms;
R 9 represents lower alkyl with 1 to 4 carbon atoms;
R 8 and R 9 together form a 5- or 6-membered heterocylic ring containing one to two hetero atoms which can be the same or different and are oxygen or nitrogen;
R 6 represents hydrogen, halogen, nitro, or lower alkyloxy;
R 7 represents hydrogen;
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 selected from the group consisting of:
5-[6,7-Dimethoxy-2-(7-methoxy-1H-indol-3-ylmethyl)-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine;
5-[6,7-Dimethoxy-2-(5-methoxy-1H-indol-3-ylmethyl)-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine;
5-[2-(1H-Indol-3-ylmethyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine;
5-[6,7-Dimethoxy-2-(2-methyl-1H-indol-3-ylmethyl)-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine;
5-[2-(6-Fluoro-1H-indol-3-ylmethyl)-6,7-dimethoxy-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine;
{3-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethyl]-1H-indol-2-yl}-morpholin-4-yl-methanone;
3-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethyl]-1H-indole-2-carboxylic acid dimethylamide;
5-[6,7-Dimethoxy-2-(5-nitro-1H-indol-3-ylmethyl)-benzofuran-4-ylmethyl]-pyrimidine-2,4-diamine;
{3-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethyl]-1H-indol-2-yl}-pyrrolidin-1-yl-methanone;
3-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethyl]-5-methoxy-1H-indole-2-carboxylic acid dimethylamide;
3-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethyl]-1H-indole-2-carboxylic acid methoxy-methyl-amide;
5-Chloro-3-[4-(2,4-diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethyl]-1H-indole-2-carboxylic acid dimethylamide;
3-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethyl]-5-fluoro-1H-indole-2-carboxylic acid dimethylamide;
5-Chloro-3-[4-(2,4-diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethyl]-1H-indole-2-carboxylic acid methoxy-methyl-amide;
3-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethyl]-1H-indole-2-carboxylic acid N,N′-dimethyl-hydrazide;
3-[4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-ylmethyl]-5-fluoro-1H-indole-2-carboxylic acid methoxy-methyl-amide;
or a pharmaceutically acceptable salt thereof.
7. An intermediate compound of formula XI and XII
wherein
R 2 and R 3 independently represent hydrogen, lower alkyl with 1 to 3 carbon atoms, or together a lower alkylene group with 1 to 3 carbon atoms bridging the oxygen atoms and forming a five, six or seven membered ring;
R 4 represents hydrogen;
R 5 is hydrogen, lower alkyl with 1 to 4 carbon atoms, or the group
wherein
R 8 represents lower alkyloxy, lower alkylamino, or lower alkyl with 1 to 4 carbon atoms;
R 9 represents lower alkyl with 1 to 4 carbon atoms;
R 8 and R 9 together form a 5- or 6-membered heterocylic ring containing one to two hetero atoms which can be the same or different and are oxygen or nitrogen;
R 6 represents hydrogen, halogen, nitro, or lower alkyloxy.
8. A pharmaceutical composition comprising one or more compounds of claim 1 and a pharmaceutically acceptable inert carrier material.
9. A process for the manufacture of a pharmaceutical composition containing one or more compounds as claimed in claim 1 as active ingredients, which process comprises mixing one or more active ingredients with a pharmaceutically acceptable inert carrier material and/or an adjuvant.
10. A process for the manufacture of a pharmaceutical composition comprising one or more compounds as claimed in claim 6 as active ingredients, which process comprises mixing one or more active ingredients with a pharmaceutically acceptable inert carrier material and/or an adjuvant.
11. A pharmaceutical composition comprising one or more compounds of claim 6 and a pharmaceutically acceptable inert carrier material.
12. A method for treating an infection caused by a bacterium that can be inhibited through inhibition of its dihydrofolate reductdase enzyme by administering to a subject in need thereof an effective amount of the compound of claim 1 .
13. The method of claim 12 , wherein the bacterium is a Gram positive pathogen or a Gram negative pathogen.
14. A method for treating an infection caused by a bacterium that can be inhibited through inhibition of its dihydrofolate reductdase enzyme by administering to a subject in need thereof an effective amount of the compound of claim 6 .
15. The method of claim 14 , wherein the bacterium is a Gram positive pathogen or a Gram negative pathogen.