IP Library › Granted Patent US 8,420,693

Granted Patent B2

US 8,420,693 · App. 11/794,488 · Granted Apr 16, 2013

Dipyrrole compounds, compositions, and methods for treating cancer or viral diseases

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Quick Facts

Patent No.: US 8,420,693
App. No.: 11/794,488
Granted: Apr 16, 2013
Kind: B2

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Abstract

The present invention relates to novel Dipyrrole Compounds, compositions comprising a Dipyrrole Compound, and methods useful for treating or preventing cancer or a neoplastic disorder comprising administering a Dipyrrole Compound. The compounds, compositions, and methods of the invention are also useful for inhibiting the growth of a cancer cell or neoplastic cell, treating or preventing a viral infection, or inhibiting the replication and/or infectivity of a virus. The invention also provides screening assays for compounds that can be used in combination with Dipyrrole Compounds for the treatment of cancer or neoplastic disease, inhibition of cancer cell growth, or treatment of viral infections.

Claims (112)

1. A composition comprising a pharmaceutically acceptable carrier or vehicle and an effective amount of a compound having the formula

or a pharmaceutically acceptable salt thereof,

wherein

R 7 is —O—(C 1 -C 8 alkyl);

R 9 is —(C 3 -C 12 ) cycloalkyl, -aryl selected from the group consisting of phenyl, tolyl, anthryl, fluorenyl, indenyl, azulenyl, phenanthryl, and naphthyl, each of which may be unsubstituted or substituted with one or more of halogen, OH, C 1-8 alkyl, O(C 1-8 alkyl), CH 2 OR 10 , S(C 1-8 alkyl), C(O)R 10 , S(O) 2 R 10 , NO 2 , or SR 10 ; —C 1 -C 10 (aryl)alkyl, or substituted or unsubstituted 3- to 12-membered heterocycle selected from the group consisting of aziridinyl, oxiranyl, thiiranyl, azirinyl, diaziridinyl, diazirinyl, oxaziridinyl, azetidinyl, azetidinonyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, morpholinyl, oxazinyl, thiazinyl, diazinyl, triazinyl, tetrazinyl, imidazolyl, tetrazolyl, isoquinolinyl, quinolinyl, quinazolinyl, pyrrolidinyl, purinyl, isoxazolyl, benzisoxazolyl, furanyl, furazanyl, pyridinyl, oxazolyl, thiazolyl, thiophenyl, pyrazolyl, triazolyl, benzodiazolyl, benzotriazolyl, pyrimidinyl, isoindolyl, indazolyl, benzodioxole, dibenzofuran and dibenzothiophene, each of which may be substituted with one or more of halogen, O(C 1-8 alkyl), or C 1-8 alkyl; and

each R 10 is independently —H, —C 1 -C 8 alkyl, —C 3 -C 12 cycloalkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkenyl.

2. The composition of claim 1 , wherein R 9 is aryl selected from the group consisting of phenyl, tolyl, anthryl, fluorenyl, indenyl, azulenyl, phenanthryl, and naphthyl, each of which may be unsubstituted or substituted with one or more of halogen, OH, C 1-8 alkyl, O(C 1-8 alkyl), CH 2 OR 10 , S(C 1-8 alkyl), C(O)R 10 , S(O) 2 R 10 , NO 2 , or SR 10 ; or substituted or unsubstituted 3- to 12-membered heterocycle selected from the group consisting of aziridinyl, oxiranyl, thiiranyl, azirinyl, diaziridinyl, diazirinyl, oxaziridinyl, azetidinyl, azetidinonyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, morpholinyl, oxazinyl, thiazinyl, diazinyl, triazinyl, tetrazinyl, imidazolyl, tetrazolyl, isoquinolinyl, quinolinyl, quinazolinyl, pyrrolidinyl, purinyl, isoxazolyl, benzisoxazolyl, furanyl, furazanyl, pyridinyl, oxazolyl, thiazolyl, thiophenyl, pyrazolyl, triazolyl, benzodiazolyl, benzotriazolyl, pyrimidinyl, isoindolyl, indazolyl, benzodioxole, dibenzofuran and dibenzothiophene, each of which may be substituted with one or more of halogen, O(C 1-8 alkyl), or C 1-8 alkyl.

3. The composition of claim 2 , wherein R 9 is selected from the group consisting of substituted and unsubstituted phenyl, quinolinyl, thiophenyl, furyl, napthyl, pyridinyl, dihydrobenzofuranyl, pyrimidinyl, dihydrooxazinylphenyl, and pyrazolyl, each of which may be substituted with one or more of halogen, OH, C 1-8 alkyl, O(C 1-8 alkyl), CH 2 OR 10 , S(C 1-8 alkyl), C(O)R 10 , S(O) 2 R 10 , NO 2 , or SR 10 .

4. The composition of claim 3 , wherein the compound is selected from the group consisting of:

3-methoxy-2-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-5-phenyl-2H-pyrrole;

5-(4-chlorophenyl)-3-methoxy-2-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-2H-pyrrole;

2-((5-(2,4-difluorophenyl)-3-methoxy-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-1H-pyrrole;

5-(4-methoxy-5-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-5H-pyrrol-2-yl)quinoline;

5-(4-fluorophenyl)-3-methoxy-2-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-2H-pyrrole;

2-((3-methoxy-5-(thiophen-2-yl)-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-1H-pyrrole;

2-((5-(5-bromothiophen-2-yl)-3-methoxy-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-1H-pyrrole;

N-4-(4-methoxy-5-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-5H-pyrrol-2-yl)-phenyl-methylsulfonamide;

4-(4-methoxy-5-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-5H-pyrrol-2-yl)benzaldehyde;

5-methoxy-2-(4-methoxy-5-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-5H-pyrrol-2-yl)benzaldehyde;

2-((3-methoxy-5-(3-nitrophenyl)-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-1H-pyrrole;

2-((5-(furan-2-yl)-3-methoxy-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-1H-pyrrole;

2-((5-(furan-3-yl)-3-methoxy-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-1H-pyrrole;

2-((3-methoxy-5-(thiophen-3-yl)-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-1H-pyrrole;

2-((3-methoxy-5-(2,4-dimethoxyphenyl)-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-1H-pyrrole;

2-((3-methoxy-5-(3,4-dimethoxyphenyl)-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-1H-pyrrole;

2-((3-methoxy-5-(2,3,4-trimethoxyphenyl)-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-1H-pyrrole;

2-((3-methoxy-5-(2,5-dimethoxyphenyl)-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-1H-pyrrole;

2-((5-(benzo[d][1,3]dioxol-5-yl)-3-methoxy-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-1H-pyrrole;

2-((5-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-3-methoxy-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-1H-pyrrole;

4-(4-methoxy-5-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-5H-pyrrol-2-yl)-N,N-dimethylbenzenamine;

2-((5-(2,3-dihydrobenzo[b][1,4]dioxin-7-yl)-3-methoxy-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-1H-pyrrole;

2-((3-methoxy-5-(4-methoxy-3-methylphenyl)-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-1H-pyrrole;

(4-(4-methoxy-5-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-5H-pyrrol-2-yl)phenyl)(pyrrolidin-1-yl)methanone;

2-((5-(3-fluoro-4-methoxyphenyl)-3-methoxy-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-1H-pyrrole;

2-((3-methoxy-5-(2-methoxynaphthalen-6-yl)-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-1H-pyrrole;

2-((3-methoxy-5-(3,4,5-trimethoxyphenyl)-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-1H-pyrrole;

2-((5-(4-bromophenyl)-3-methoxy-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-1H-pyrrole;

2-methoxy-3-(4-methoxy-5-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-5H-pyrrol-2-yl)pyridine;

2-((5-(2,3-dihydrobenzofuran-6-yl)-3-methoxy-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-1H-pyrrole;

2,4-dimethoxy-5-(4-methoxy-5-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-5H-pyrrol-2-yl)pyrimidine;

2-chloro-3-(4-methoxy-5-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-5H-pyrrol-2-yl)pyridine;

3,4-dihydro-7-(4-methoxy-5-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-5H-pyrrol-2-yl)-4-methyl-2H-benzo[b][1,4]oxazine;

5-(4-methoxy-5-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-5H-pyrrol-2-yl)pyrimidine;

2-((5-(4-(isopropylthio)phenyl)-3-methoxy-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-1H-pyrrole;

1-benzyl-4-(4-methoxy-5-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-5H-pyrrol-2-yl)-1H-pyrazole;

2-methoxy-5-(4-methoxy-5-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-5H-pyrrol-2-yl)phenol;

2-fluoro-5-(4-methoxy-5-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-5H-pyrrol-2-yl)pyridine;

2-fluoro-3-(4-methoxy-5-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-5H-pyrrol-2-yl)pyridine;

2-((5-(4-(tert-butoxymethyl)phenyl)-3-methoxy-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-1H-pyrrole;

2-methoxy-5-(4-methoxy-5-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-5H-pyrrol-2-yl)pyridine;

3-(benzyloxy)-5-(3,4-dimethoxyphenyl)-2-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-2H-pyrrole; and

5-(benzo[d][1,3]dioxol-5-yl)-3-(benzyloxy)-2-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-2H-pyrrole.

5. A compound of the formula

or a pharmaceutically acceptable salt thereof,

wherein

R 7 is —O—(C 1 -C 8 alkyl);

each R 10 is independently —H, —C 1 -C 8 alkyl, —C 3 -C 12 cycloalkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 9 is aryl selected from the group consisting of phenyl, tolyl, anthryl, fluorenyl, indenyl, azulenyl, phenanthryl, and naphthyl, each of which may be unsubstituted or substituted with one or more of halogen, OH, C 1-8 alkyl, O(C 1-8 alkyl), CH 2 OR 10 , S(C 1-8 alkyl), C(O)R 10 , S(O) 2 R 10 , NO 2 , or SR 10 , or substituted or unsubstituted 3- to 12-membered heterocycle selected from the group consisting of aziridinyl, oxiranyl, thiiranyl, azirinyl, diaziridinyl, diazirinyl, oxaziridinyl, azetidinyl, azetidinonyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, morpholinyl, oxazinyl, thiazinyl, diazinyl, triazinyl, tetrazinyl, imidazolyl, tetrazolyl, isoquinolinyl, quinolinyl, quinazolinyl, pyrrolidinyl, purinyl, isoxazolyl, benzisoxazolyl, furanyl, furazanyl, pyridinyl, oxazolyl, thiazolyl, thiophenyl, pyrazolyl, triazolyl, benzodiazolyl, benzotriazolyl, pyrimidinyl, isoindolyl, indazolyl, benzodioxole, dibenzofuran and dibenzothiophene, each of which may be unsubstituted or substituted with one or more of halogen, O(C 1-8 alkyl), or C 1-8 alkyl.

7. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 9 is aryl selected from substituted and unsubstituted phenyl, anthryl, fluorenyl, indenyl, azulenyl, phenanthryl and naphthyl, each of which may be substituted with one or more of halogen, O(C 1-8 alkyl), or C 1-8 alkyl.

8. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 9 is substituted or unsubstituted 3- to 12-membered heterocycle selected from the group consisting of substituted and unsubstituted aziridinyl, oxiranyl, thiiranyl, azirinyl, diaziridinyl, diazirinyl, oxaziridinyl, azetidinyl, azetidinonyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, morpholinyl, oxazinyl, thiazinyl, diazinyl, triazinyl, tetrazinyl, imidazolyl, tetrazolyl, isoquinolinyl, quinolinyl, quinazolinyl, pyrrolidinyl, purinyl, isoxazolyl, benzisoxazolyl, furanyl, furazanyl, pyridinyl, oxazolyl, thiazolyl, thiophenyl, pyrazolyl, triazolyl, benzodiazolyl, benzotriazolyl, pyrimidinyl, indazolyl, benzodioxole, dibenzofuran and dibenzothiophene, each of which may be substituted with one or more of halogen, O(C 1-8 alkyl), or C 1-8 alkyl.

9. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 9 is selected from the group consisting of substituted and unsubstituted phenyl, quinolinyl, thienyl, furyl, napthyl, pyridinyl, dihydrobenzofuranyl, pyrimidinyl, dihydrooxazinylphenyl, and pyrazolyl, each of which may be substituted with one or more of halogen, OH, C 1-8 alkyl, O(C 1-8 alkyl), CH 2 OR 10 , S(C 1-8 alkyl), C(O)R 10 , S(O) 2 R 10 , NO 2 , or SR 10 .

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R 7 is —OCH 3 .

11. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 7 is —OCH 3 .

12. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 7 is —O—(C 1 -C 8 alkyl) substituted with phenyl.

13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein R 7 is —O-benzyl.

14. The compound of claim 5 , wherein the compound is selected from the group consisting of: