# US 9,518,051 B2 · Pyrroloquinoline alkaloids as antimalarial agents and process for the preparation thereof

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- Number: US 9,518,051 B2
- Document ID: US9518051B2
- Status: Granted
- Kind: B2
- Application number: 14/377,407
- Filed: 2013-02-08
- Published: 2015-11-26
- Granted: 2016-12-13
- Earliest claimed: 2012-02-08
- Assignees: Council of Scientific and Industrial Research
- Applicants: Council of Scientific & Industrial Research
- Inventors: Santosh Baburao Mhaske; Jyoti Reveji Lande
- Web page: https://patentgrep.com/patent/US9518051B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 31/06: for tuberculosis
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The patent provides novel compounds with potential anti-malarial activity and process of synthesis thereof. Further, the process for the synthesis of known antimalarial natural products marinoquinazolinone A-F, aplidiopsamine A and their potential antimalarial analogs is disclosed.

## Claims

### Claim 1

A compound of formula I or a pharmaceutically acceptable salt thereof,
wherein R, R1, and R2 are selected from the group consisting of H, halide, alkyl, aryl, hetero alkyl, and hetero aryl,
X is H, halide, OTf, or OTs,
R3 is a compound of formula III,
and
R4 is selected from the group consisting of H, halide, alkyl, aryl, hetero alkyl, and hetero aryl.

### Claim 2 (depends on 1)

A process for the preparation of compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1,
comprising the steps of:
a. refluxing a ketone of formula
with an aniline of formula
wherein R, R1, R2 and R4 are each selected from the group consisting of H, halide, alkyl, aryl, hetero alkyl, and hetero aryl;
R3 is a compound of formula III,
and
X is H, halide, OTf, or OTs,
in mole ratio 1:1 in a solvent for a period ranging between 12-24 hrs followed by work up to obtain a corresponding imine of formula
b. reacting the corresponding imine of step (a) in the presence of a Pd catalyst, a ligand, a base and a solvent at temperature ranging between 100-120° C. for a period between 8-24 hrs to obtain a compound of formula

### Claim 3 (depends on 2)

The process as claimed in claim 2, wherein the yield is in the range of 40% to 98%.

### Claim 4 (depends on 2)

The process as claimed in claim 2, wherein the Pd catalyst is Pd(OAc)2 in the range of 1 mol % to 20 mol %.

### Claim 5 (depends on 2)

The process as claimed in claim 2, wherein the ligand is selected from the group consisting of triphenyl phosphate, Neocuproine and tricyclohexyl phosphine.

### Claim 6 (depends on 2)

The process as claimed in claim 2, wherein the ligand is PPh3 in the range of 1 mol % to 40 mol %.

### Claim 7 (depends on 2)

The process as claimed in claim 2, wherein the base is selected from the group consisting of K2CO3, Cs2CO3, Ag2CO3 and KOtBu.

### Claim 8 (depends on 2)

The process as claimed in claim 2, wherein the base is Ag2CO3 in the range of 1 mol % to 200 mol %.

### Claim 9 (depends on 2)

The process as claimed in claim 2, wherein the solvent is selected from the group consisting of 1,4-dioxane, dry toluene, DMF, Benzene and THF.

### Claim 10

A method of treating malaria comprising the step of administering a compound of formula I or a pharmaceutically acceptable salt thereof,
wherein R, R1, and R2 are selected from the group consisting of H, halide, alkyl, aryl, hetero alkyl, and hetero aryl,
X is H, halide, OTf, or OTs,
R3 is a compound of formula III, and
R4 is selected from the group consisting of H, halide, alkyl, aryl, hetero alkyl, and hetero aryl.