Polysubstituted pyrroles having microtubule-disrupting, cytotoxic and antitumor activities and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9944597-B2
Application number	US-201415021972-A
Country	US
Kind code	B2
Filing date	Sep 16, 2014
Priority date	Sep 16, 2013
Publication date	Apr 17, 2018
Grant date	Apr 17, 2018

Abstract

The present invention provides polysubstituted pyrrole compounds, pharmaceutically effective salts, prodrugs, solvates and hydrates thereof, having antimitotic, antiproliferative and cytotoxic activity, activity against cells expressing the drug efflux protein, P-glycoprotein, or cells expressing the β-III isotype of tubulin and antitumor activity. Also provided are methods of utilizing these compounds for inhibiting the proliferation of cancer cells as well as their medical use, in particular for treating cancer, including drug resistant cancer.

First claim

What is claimed is:

1. A compound of Formula II:

or its pharmaceutically acceptable salt, solvate or hydrate, wherein:
Z is H;
X′ is independently selected from the group halo;
R 2 is independently selected from the group consisting of —C(O)—OR 3 and cyano;
R 3 is independently selected from the group consisting of C 1 -C 5 straight alkyl;
R 8 is independently selected from the group consisting of HC(NOR 7 ), C 1 -C 5 straight alkyl, C 3 -C 5 branched alkyl, C 3 -C 5 cyclic alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amidoalkyl, carboxyalkyl, alkoxycarbonylalkyl, acyloxyalkyl, sulfonylalkyl, heteroaryl, heteroaroyl, heteroaralkyl, heterocycle, —(CO)heterocycle and heterocyclicalkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, acyl, alkanoyl, hydroxy, alkoxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, aminoalkyl, alkylamino, imino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —OPO 3 H 2 , —PO 4 H 2 , —PO 3 H 2 , —P(R 7 )O 2 H, —OSO 3 H, —SO 3 H, and oximino, O-methyl-oximino, O-ethyl-oximino, O-n-propyl-oximino;
R 7 is independently selected from the group consisting of alkyl, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, oxo, alkoxy, hydroxy, hydroxyalkyl, imino, amino, aminoalkyl, and carboxy.

2. The compound of claim 1 , wherein:
R 8 is independently selected from the group consisting of HC(NOR 7 ), amidoalkyl, aminoalkyl, and alkylaminoalkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of acyl, alkanoyl, hydroxy, alkoxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, imino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —OPO 3 H 2 , —PO 4 H 2 , —PO 3 H 2 , —P(R 7 )O 2 H, —OSO 3 H, —SO 3 H, and oximino.

3. The compound of claim 1 , wherein:
X′ is bromo or chloro;
R 3 is independently selected from the group consisting of methyl, ethyl and n-propyl;
R 8 is independently selected from the group consisting of oximino, O-methyl-oximino, O-ethyl-oximino, O-n-propyl-oximino, aminomethyl, aminoethyl, aminopropyl, aminobutyl, methylaminomethyl, ethylaminomethyl, propylaminomethyl, butylaminommethyl, methylaminoethyl, ethylaminoethyl, propylaminoethyl, butylaminoethyl, methylaminopropyl, ethylaminopropyl, propylaminopropyl, butylaminopropyl, methylaminobutyl, ethylaminobutyl, propylaminobutyl and butylaminobutyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of acyl, alkanoyl, hydroxy, alkoxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, imino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —OPO 3 H 2 , —PO 4 H 2 , —PO 3 H 2 , —P(R 7 )O 2 H, —OSO 3 H, and —SO 3 H.

4. The compound of claim 1 , wherein the compound is selected from the group consisting of:
5-Oximino-3-bromo-4-(2,3,4-trimethoxyphenyl)-1H-pyrrole 2-carboxylic acid ethyl ester, 5-(O-Methyl-oximino)-3-bromo-4-(2, 3 ,4-trimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester, 5 -Oximino-3-chloro-4-(2,3 ,4-trimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(Aminomethylene)-3-bromo-4-(2, 3 ,4-trimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester; 5-(Aminomethylene)-3-chloro-4-(2,3 ,4-trimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester; 5-(n-Propylaminomethylene)-3-Bromo-4-(2, 3 , 4-trimethoxyphenyl)-1H -pyrrole-2 -carboxylic acid ethyl ester; 5-(n-Propylaminomethylene)-3-Chloro-4-(2, 3 ,4-trimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester; 5-[N-((2-Aminoethyl)amino)methylene]-3-bromo-4 -(2,3 ,4-trimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester; and 5-[((N-2-tert -butoxycarbonylamino)-ethylamino)-methylene]-3-bromo-4-(2,3,4-trimethoxy-phenyl)-1H-pyrrole 2-carboxylic acid ethyl ester.

5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition of claim 5 , in a form suitable for oral, parenteral, intravenous, intradermal, transdermal, subcutaneous or topical administration.

7. A method of treating a breast cancer patient comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .

8. The method of claim 7 , wherein the compound is selected from the group consisting of:
5-Oximino-3-bromo-4-(2, 3 ,4-trimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester; 5 -(O-Methyl -oximino)-3-bromo-4-(2, 3 ,4-trimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester; 5-Oximino-3-chloro-4-(2,3 ,4-trimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester; 5-(Aminomethylene)-3-bromo-4-(2, 3 ,4-trimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester; 5-(Aminomethylene)-3-chloro-4-(2,3 ,4-trimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester; 5-(n-Propylaminomethylene)-3-Bromo -4- (2, 3 , 4-trimethoxyphenyl)-1H-pyrrole-2 -carboxylic acid ethyl ester;
5-(n-Propylaminomethylene)-3-Chloro-4-(2, 3 ,4-trimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester; 5-[N-((2-Aminoethyl)amino)methylene]-3-bromo-4-(2,3,4-trimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester; and 5-[((N-2-tert-butoxycarbonylamino)-ethylamino) -methylene]-3-bromo-4-(2,3 ,4-trimethoxy-phenyl)-1H-pyrrole 2-carboxylic acid ethyl ester.

9. A compound of Formula I:

wherein:
X and Y are the same and are independently selected from the group halo;
R 2 is independently selected from the group consisting of —C(O)—OR 3 ;
R 3 is independently selected from the group consisting of C 1 -C 5 straight alkyl.

10. The compound of claim 9 wherein:
X and Y are the same and are selected from the group consisting of bromo and chloro; and
R 3 is independently selected from the group consisting of methyl, ethyl and n-propyl.

11. The compound of claim 9 , wherein the compound is 3,5-Dibromo-4-(2,3,4 -trimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester; and 3,5-Dichloro-4-(2,3,4 -trimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester.

12. A method of treating a breast cancer patient comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 9 .

13. The method of claim 12 , wherein the compound is 3,5-Dibromo-4-(2,3, -trimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester; 3,5-Dichloro-4-(2,3,4-trimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester; or 2-Cyano-3,5-Dibromo-4-(2,3,4-trimethoxyphenyl)-1H-pyrrole.

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 9 and a pharmaceutically acceptable carrier.

15. The pharmaceutical composition of claim 14 in a form suitable for oral, parenteral, intravenous, intradermal, transdermal, subcutaneous or topical administration.

Assignees

• Kellogg Glen E
• Da Chenxiao
• Tripathi Ashutosh
• Gupton John T
• Telang Nakul
• Sikorski James A
• Mooberry Susan L
• Rohena Cristina
• Univ Texas
• Univ Virginia Commonwealth
• Univ Of Richmond

Inventors

• Kellogg Glen E
• Da Chenxiao
• Tripathi Ashutosh
• Gupton John T
• Telang Nakul
• Sikorski James A
• Mooberry Susan L
• Rohena Cristina

Classifications

• C07D207/36

  Oxygen or sulfur atoms · CPC title

• C07D403/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D207/46

  with hetero atoms directly attached to the ring nitrogen atom · CPC title