Bicycle topoisomerase i inhibiting compounds, process for preparation and use thereof

Patent metadata

Field	Value
Publication number	US-12172991-B2
Application number	US-201917059289-A
Country	US
Kind code	B2
Filing date	May 24, 2019
Priority date	May 29, 2018
Publication date	Dec 24, 2024
Grant date	Dec 24, 2024

Abstract

The invention described herein relates to the compounds of Formula I for treating diseases and disorders for which inhibition or modulation of the topoisomerase I enzyme produces a physiologically beneficial response, in particular for the treatment of breast cancer. Also provided is the process of preparing compounds of Formula I.

First claim

We claim:

1. A compound of Formula I or salts thereof,

wherein:
R 1 is a substituted aromatic heterocyclic group selected from the group consisting of oxadiazole, pyridyl, amino pyridyl, and furyl, wherein the aromatic heterocyclic group is substituted with —CH 3 or —NH 2 ;
R 2 is a water soluble or hydrophilic functional group —NR 5 R 6 ;
R 5 and R 6 are either same or different selected from hydrogen atom, a substituted C 1 -C 6 alkyl chain bearing nitrogen containing aromatic heterocyclic group, or a substituted C 1 -C 6 alkyl chain bearing nitrogen containing aliphatic heterocyclic group;
R 3 is selected from hydrogen, halogen, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, amino, alkylamino, acyl amino, or carbamate;
X is CH; and
n is 0-3.

2. The compound as claimed in claim 1 , wherein the compound is selected from:
6-(4-methoxyphenyl)-N-(2-morpholinoethyl)-3-(1,3,4-oxadiazol-2-yl)quinolin-4-amine (9);
6-(4-methoxyphenyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-morpholinoethyl)quinolin-4-amine (14);
N-(3-(1H-imidazol-1-yl)propyl)-6-(4-methoxyphenyl)-3-(1,3,4-oxadiazol-2-yl)quinolin-4-amine (18);
N-(3-(1H-imidazol-1-yl)propyl)-6-(3,4-dimethoxyphenyl)-3-(1,3,4-oxadiazol-2-yl)quinolin-4-amine (19);
N-(3-(1H-imidazol-1-yl)propyl)-6-(4-aminophenyl)-3-(1,3,4-oxadiazol-2-yl)quinolin-4-amine (20);
4-(4-((3-(1H-imidazol-1-yl)propyl)amino)-3-(1,3,4-oxadiazol-2-yl)quinolin-6-yl)benzonitrile (21);
4-(4-((3-(1H-imidazol-1-yl)propyl)amino)-3-(1,3,4-oxadiazol-2-yl)quinolin-6-yl)phenol (22);
N-(3-(1H-imidazol-1-yl)propyl)-6-(4-methoxy-3-methylphenyl)-3-(1,3,4-oxadiazol-2-yl)quinolin-4-amine (28);
N-(3-(1H-imidazol-1-yl)propyl)-3-(1,3,4-oxadiazol-2-yl)-6-(p-tolyl)quinolin-4-amine (29);
N-(3-(1H-imidazol-1-yl)propyl)-6-(4-methoxy-2-methylphenyl)-3-(1,3,4-oxadiazol-2-yl)quinolin-4-amine (31);
N-(3-(1H-imidazol-1-yl)propyl)-6-(4-methoxy-2,6-dimethylphenyl)-3-(1,3,4-oxadiazol-2-yl)quinolin-4-amine (32);
N-(3-(1H-imidazol-1-yl)propyl)-6-(4-ethoxyphenyl)-3-(1,3,4-oxadiazol-2-yl)quinolin-4-amine (34);
N-(3-(1H-imidazol-1-yl)propyl)-6-(4-ethylphenyl)-3-(1,3,4-oxadiazol-2-yl)quinolin-4-amine (35);
N-(3-(1H-imidazol-1-yl)propyl)-6-(4-isopropoxyphenyl)-3-(1,3,4-oxadiazol-2-yl)quinolin-4-amine (36);
N-(3-(1H-imidazol-1-yl)propyl)-6-(4-isopropylphenyl)-3-(1,3,4-oxadiazol-2-yl)quinolin-4-amine (37);
6-(4-methoxyphenyl)-N-(3-morpholinopropyl)-3-(1,3,4-oxadiazol-2-yl)quinolin-4-amine (43);
N-(3-morpholinopropyl)-3-(1,3,4-oxadiazol-2-yl)-6-(p-tolyl)quinolin-4-amine (44a);
6-(3,4-dimethoxyphenyl)-N-(3-morpholinopropyl)-3-(1,3,4-oxadiazol-2-yl)quinolin-4-amine (45a);
N-(2-(1H-imidazol-1-yl)ethyl)-6-(4-methoxyphenyl)-3-(1,3,4-oxadiazol-2-yl)quinolin-4-amine (50);
5-(4-((3-(1H-imidazol-1-yl)propyl)amino)-6-(4-methoxyphenyl)quinolin-3-yl)-1,3,4-oxadiazol-2-amine (52);
N-(3-(1H-imidazol-1-yl)propyl)-6-(4-methoxyphenyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)quinolin-4-amine (54);
N-(3-(1H-pyrrol-1-yl)propyl)-6-(4-methoxyphenyl)-3-(1,3,4-oxadiazol-2-yl)quinolin-4-amine (58);
6-(4-methoxyphenyl)-3-(1,3,4-oxadiazol-2-yl)-N-(3-(pyrrolidin-1-yl)propyl)quinolin-4-amine (62);
N-(3-(1H-imidazol-1-yl)propyl)-3-(furan-2-yl)-6-(4-methoxyphenyl)quinolin-4-amine (70);
N-(3-(1H-imidazol-1-yl)propyl)-3-(6-aminopyridin-3-yl)-6-(4-methoxyphenyl)quinolin-4-amine (73);
N-(3-(1H-imidazol-1-yl)propyl)-3-(1,3,4-oxadiazol-2-yl)-6-(4-(trifluoromethyl)phenyl)quinolin-4-amine (79);
N-(3-(1H-imidazol-1-yl)propyl)-6-(4-(dimethylamino)phenyl)-3-(1,3,4-oxadiazol-2-yl)quinolin-4-amine (80);
N-(3-(1H-imidazol-1-yl)propyl)-3-(1,3,4-oxadiazol-2-yl)-6-(4-(trifluoromethoxy)phenyl)quinolin-4-amine (81);
N-(3-(1H-imidazol-1-yl)propyl)-6-(3-methoxyphenyl)-3-(1,3,4-oxadiazol-2-yl)quinolin-4-amine (82);
N-(3-(1H-imidazol-1-yl)propyl)-6-(2-methoxyphenyl)-3-(1,3,4-oxadiazol-2-yl)quinolin-4-amine (83);
tert-butyl (4-(4-((3-(1H-imidazol-1-yl)propyl)amino)-3-(1,3,4-oxadiazol-2-yl)quinolin-6-yl)phenyl)(methyl)carbamate (84);
N-(3-(1H-imidazol-1-yl)propyl)-6-(4-(methylamino)phenyl)-3-(1,3,4-oxadiazol-2-yl)quinolin-4-amine (85); and
N-(4-(4-((3-(1H-imidazol-1-yl)propyl)amino)-3-(1,3,4-oxadiazol-2-yl)quinolin-6-yl)phenyl)acetamide (86).

3. A process of preparation of the compound of Formula I as claimed in claim 1 comprising reacting a compound of Formula II

with a boronic acid of Formula V or Formula VI

 or

in presence of a 2(M) sodium carbonate solution and a tetrakis(triphenylphosphine)palladium(0) catalyst in a solvent to obtain the compound of Formula I,

wherein R 1 -R 3 , n and X are as defined in claim 1 .

4. The process of preparation of compound of Formula I as claimed in claim 3 , wherein R 1 of the Formula I is

the process comprising:
(i) reacting a 4-bromoaniline (compound 1) with a diethyl ethoxymethylenemalonate at 120° C. for 2 hours to obtain a diethyl 2-((4-bromophenylamino)methylene)malonate (compound 2);
(ii) heating the compound 2 in a dowtherm solvent at 240° C. for 2.5 hours to obtain a ethyl 6-bromo-4-hydroxyquinoline-3-carboxylate (compound 3);
(iii) reacting the compound 3 with a chlorinating agent at 100° C. for 2 hours to produce an ethyl 6-bromo-4-chloroquinoline-3-carboxylate (compound 4);
(iv) reacting the compound 4 with an amine selected from the group consisting of -(2-aminoethyl)morpholine, 3-(1H-imidazol-1-yl)propan-1-amine, 3-morpholinopropan-1-amine, 2-(1H-imidazol-1-yl)ethanamine, 3-(1H-pyrrol-1-yl)propan-1-amine, 3-(pyrrolidin-1-yl)propan-1-amine and methylamine in presence of DIPEA to obtain a compound of Formula III;

(v) reacting the compound of Formula III as obtained in previous step with a hydrazine monohydrate in ethanol at room temperature to obtain a compound of Formula IV;

(vi) heating the compound of Formula IV with triethylorthoformate or triethylorthoacetate to obtain a compound of formula IIA;

wherein A is H or methyl group, and

(vii) reacting the compound of Formula IIA with the boronic acid of formula V or formula VI

 or

in presence of the 2(M) sodium carbonate solution and the tetrakis(triphenylphosphine)palladium(0) catalyst in a solvent to obtain the compound of formula IA,

wherein R 2 , R 3 , X and n are as defined in claim 1 .

5. The process of preparation of

Assignees

• Council Scient Ind Res
• Indian Ass For The Cultivation Of Science

Inventors

• Talukdar Arindam
• Das Benu Brata
• Kundu Biswajit
• Das Subhendu K
• Paul Chowdhuri Srijita
• Sarkar Dipayan
• Pal Sourav
• Bhattacharya Debomita
• Mukherjee Ayan
• Roy Subhajit

Classifications

• C07D491/22

  in which the condensed system contains four or more hetero rings · CPC title

• C07D413/04

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

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/12

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

• C07D405/14

  containing three or more hetero rings · CPC title