# US 7,608,615 B2 · Pyrrolo[2,1-C][1,4]benzodiazepine hybrids and a process for the preparation thereof

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 7,608,615 B2
- Document ID: US7608615B2
- Status: Granted
- Kind: B2
- Application number: 11/893,380
- Filed: 2007-08-14
- Published: 2008-03-13
- Granted: 2009-10-27
- Earliest claimed: 2006-08-14
- Assignees: Council of Scientific and Industrial Research
- Inventors: Kamal Ahmed; Venkata Ramana Adhi; Hari Babu Ankati
- Web page: https://patentgrep.com/patent/US7608615B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides quinazolinone linked pyrrolo[2,1-c][1,4]benzodiazepine hybrid of general formula 5, wherein, R is alkyl or halo group selected from H, Cl, F or CH3 and n=1 to 3 useful for antitumour/anticancer activity. The present invention also provides a process for the preparation of quinazolinone linked pyrrolo[2,1-c][1,4]benzodiazepine hybrid general formula 5.

## Claims

### Claim 1

A compound having formula 5:
wherein R is selected from the group consisting of H, Cl, F and CH3; and n =1, 2, 3 or 4.

### Claim 2 (depends on 1)

The compound according to claim 1 wherein the compound is selected from the group consisting of:
7-Methoxy-8-[3-(6-H-2-oxo-4-phenyl-1,2-dihydro- 1 -quinazolinyl)propoxy]-(11 aS)-1,2,3,11 a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one (5a);
7-Methoxy-8-[4-(6-H-2-oxo-4-phenyl-1,2-dihydro- 1-quinazolinyl)butyloxy]-(11 aS)-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one (5b);
7-Methoxy-8-[5-(6-H-2-oxo-4-phenyl-1,2-dihydro- 1 -quinazolinyl)pentyl oxy]-(11 aS)-1,2,3,11 a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one (5c);
7-Methoxy-8-[3-(6-chloro-2-oxo-4-phenyl-1,2-dihydro-1 -quinazolinyl)propoxy]-(11 aS)-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one (5d);
7-Methoxy-8-[4-(6-chloro-2-oxo-4-phenyl- 1,2-dihydro- 1 -quinazolinyl)butyloxy]-(11 aS)-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one (5e);
7-Methoxy-8-[5-(6-chloro-2-oxo-4-phenyl-1,2-dihydro-1 -quinazolinyl)pentyl oxy]-(11 aS)-1,2,3,11 a-tetrahydro-5H-pyrrolo[2, 1-c][1,4]benzodiazepine-5-one (5f);
7-Methoxy-8-[3-(6-floro-2-oxo-4-phenyl-1,2-dihydro-1 -quinazolinyl)propoxy]-(11 aS)-1,2,3,11 a-tetrahydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-5-one (5g);
7-Methoxy-8-[4-(6-floro-2-oxo-4-phenyl-1,2-dihydro-1 -quinazolinyl)butyloxy]-(11 aS)-1,2,3,11 a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one (5h);
7-Methoxy-8-[5-(6-floro-2-oxo-4-phenyl-1,2-dihydro-1-quinazolinyl)pentyl oxy]-(11 aS)-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one (5i);
7-Methoxy-8-[3-(6-methyl-2-oxo-4-phenyl-1,2-dihydro-1-quinazolinyl)propoxy]-(11 aS)-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one (5j);
7-Methoxy-8- [4-(6-methyl-2-oxo-4-phenyl-1,2-dihydro-1-quinazolinyl)butyloxy]-(11 aS)-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one (5k); and
7-Methoxy-8-[5-(6-methyl-2-oxo-4-phenyl-1,2-dihydro-1-quinazolinyl)pentyl oxy]-(11 aS)-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one (5l).

### Claim 3 (depends on 2)

The compound according to claim 2, wherein the compound has the structural formula selected from the group consisting of the formulae 5a-c, 5d-f, 5g-i, and 5-j-l:
with the further proviso that in each of the formulae 5a-c, 5d-f, 5g-i, and 5-j-l, n=1, 2 or 3.

### Claim 4 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or derivatives, analogues, salts or mixtures thereof, the composition optionally further including pharmaceutically acceptable carriers, adjuvants and/or additives.

### Claim 5 (depends on 4)

The pharmaceutical composition according to claim 4, wherein n=1, 2 or 3.

### Claim 6

A process for the preparation of a compound of formula 5:
wherein R is selected from the group consisting of H, Cl, F and CH3; and n=1, 2 or 3, said process comprising the steps of:
a) reacting (2S)-N-(4-hydroxy-3 -methoxy-2-nitrobenzoyl)pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula 2
with 1-(3 -bromo alkyl)-6-R-4-phenyl-1,2-dihydro-2-quinazolinone of formula 1,
wherein R is selected from the group consisting of H, Cl, F and CH3 and n=1, 2 or 3, in an aprotic water miscible organic solvent,
in the presence of anhydrous mild inorganic base, under refluxing temperature in an oil bath, for a period of about 48 hrs, followed by the removal of inorganic base by filtration and evaporating the organic solvent to obtain the resultant crude product and purifying it by known method to obtain the desired product of 2S-N-{4-[3-(6-R-4-phenyl- 1,2-dihydro-2-quinazolinone)]alkyl]oxy-5-methoxy-2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula 3, wherein n=1, 2 or 3
b) reducing 2S-N-{4-[3-(6-R-4-phenyl-1,2-dihydro-2-quinazolinone)]alkyl]oxy-5-methoxy-2-nitrobenzoyl }pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula 3 with anhydrous tin chloride, in an alcohol, under reflux, followed by the evaporation of alcohol and adjusting the pH of the resultant product layer to about 8 by using a base, followed by extraction with ethyl acetate and washing the combined organic phase with brine solution and evaporating the solvent to obtain the desired 2S-N- {4-[3 -(6-chloro-4-phenyl- 1,2-dihydro-2-quinazolinone)]alkyl]oxy-5-methoxy-2-aminobenzoyl}pyrrolidine -2-carboxaldehyde diethyl thioacetal of formula formula 4, wherein R is selected from the group consisting of H, Cl, F and CH3and n=1, 2 or 3,
c) reacting 2S-N- {4-[3-(6-chloro-4-phenyl-1,2-dihydro-2-quinazolinone)]alkyl]oxy-5-methoxy-2-aminobenzoyl }pyrrolidine-2-carboxaldehyde diethylthioacctal of formula 4 with mercurous chloride, in a mixture of water and organic solvent, in the presence of mild inorganic, under stirring, at a temperature of about 20-30° C., for a period of 8-12 hrs, followed by the extraction of yellow organic supernatant and washing with sodium bi carbonate and brine, respectively, and evaporating the organic layer, under reduced pressure to obtain the desired product of formula 5.

### Claim 7 (depends on 6)

The process according to claim 6, wherein the mild inorganic base used in steps (a) & (b) is potassium carbonate.

### Claim 8 (depends on 6)

The process according to claim 6, wherein the aprotic organic solvent used in step (a) is acetone and acetonitrile.

### Claim 9 (depends on 6)

The process according to claim 6, wherein the organic solvent used in step (c) is acetonitrile.

### Claim 10 (depends on 6)

The A process according to claim 6, wherein the alcohol used in step (b) is selected from methanol and ethanol.

### Claim 11 (depends on 6)

The process according to claim 6, wherein the compound of formula 5 obtained thereby is selected from the group consisting of:
7-Methoxy-8-[3-(6-H-2-oxo-4-phenyl-1,2-dihydro- 1-quinazolinyl)propoxy]-(11aS)-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one (5a);
7-Methoxy-8-[4-(6-H-2-oxo-4-phenyl-1,2-dihydro- 1-quinazolinyl)butyloxy]-(11aS)-1,2,3,11a-tetrahydro-5H-pyrrolo[2, 1-c][1,4]benzodiazepine-5-one (5b);
7-Methoxy-8-[5-(6-H-2-oxo-4-phenyl-1,2-dihydro-1-quinazolinyl)pentyl oxy]-(11aS)-1,2,3,11 a-tetrahydro-51-J-pyrrolo [2,1-c][1,4]benzodiazepine-5-one (5c);
7-Methoxy-8-[3-(6-chloro-2-oxo-4-phenyl-1,2-dihydro-1-quinazolinyl)propoxy]-(11aS)-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one(5d);
7-Methoxy-8-[4-(6-chloro-2-oxo-4-phenyl-1,2-dihydro-1-quinazolinyl)butyloxy]-(11aS)-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one (5e);
7-Methoxy-8-[5-(6-chloro-2-oxo-4-phenyl-1,2-dihydro-1 -quinazolinyl)pentyl oxy]-(11 aS)-1,2,3,11a-tetrahydro-511-pyrrolo [2,1-c][1,4]benzodiazepine-5-one (51f);
7-Methoxy-8-[3-(6-floro-2-oxo-4-phenyl-1,2-dihydro-1-quinazolinyl)propoxy]-(11aS)-1,2,3,11a-tetrahydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-5-one(5g);
7-Methoxy-8-[4-(6-floro-2-oxo-4-phenyl-1,2-dihydro- 1-quinazolinyl)butyloxy]-(11aS)-1,2,3,11a-tetrahydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-5 -one (5h);
7-Methoxy-8-[5-(6-floro-2-oxo-4-phenyl-1,2-dihydro- 1-quinazolinyl)pentyl oxy]-(11aS)-1,2,3,11a-tetrahydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-5-one (5i);
7-Methoxy-8-[3-(6-methyl-2-oxo-4-phenyl-1,2-dihydro-1-quinazolinyl)propoxy]-(11aS)-1,2,3,11a-tetrahydro-5H-pyrrolo[2, 1-c][1,4]benzodiazepine-5-one (5j);
7-Methoxy-8-[4-(6-methyl-2-oxo-4-phenyl-1,2-dihydro-1-quinazolinyl)butyloxy]-(11aS)-1,2,3,11a-tetrahydro-5H -pyrrolo[2,1-c][1,4]benzodiazepine-5-one (5k) and
7-Methoxy-8-[5-(6-methyl-2-oxo-4-phenyl-1,2-dihydro-1-quinazolinyl)pentyl oxy]-(11 aS)-1,2,3,11a-tetrahydro-5H -pyrrolo [2,1-c][1,4]benzodiazepine-5-one (5l).

### Claim 12

A method for inhibiting the growth of cancer cells, comprising contacting human cancer cells selected from the group consisting of lung, cervix, breast, colon, prostate and oral cells, with a compound having formula 5:
wherein R is selected from the group consisting of H, Cl, F and CH3; and n=1, 2, 3 or 4, and observing the effect of the compound on cell growth.

### Claim 13 (depends on 12)

The method according to claim 12, wherein the concentration of the compound used against Colo205 for IC50 is in the range of 8 to 15 μm, at an exposure period of at least 48 hrs.

### Claim 14 (depends on 12)

The method according to claim 12, wherein the concentration of the compound used against DU145 for IC50 is in the range of 8 to 15 μm, at an exposure period of at least 48 hrs.

### Claim 15 (depends on 12)

The method according to claim 12, wherein the concentration of the compound used against DWD for IC50 is in the range of 8 to 10 μm, at an exposure period of at least 48 hrs.

### Claim 16 (depends on 12)

The method according to claim 12, wherein the concentration of the compound used against HoP62 for IC50 is 5 μm, at an exposure period of at least 48 hrs.

### Claim 17 (depends on 12)

The method according to claim 12, wherein the concentration of the compound used against HT1080 for IC50 is in the range of 8 to 9 μm, at an exposure period of at least 48 hrs.

### Claim 18 (depends on 12)

The method according to claim 12, wherein the concentration of the compound used against MCF7 for IC50 is in the range of 8 to 12 μm, at an exposure period of at least 48 hrs.

### Claim 19 (depends on 12)

The method according to claim 12, wherein the concentration of the compound used against PC3 for IC50 is in the range of 7 to 11 μm, at an exposure period of at least 48 hrs.

### Claim 20 (depends on 12)

The compound according to claim 12, wherein the concentration of the compound used against SiHa for IC50 is in the range of 8 to 15 μm, at an exposure period of at least 48 hrs.

### Claim 21 (depends on 12)

The method according to claim 12, wherein the concentration of the compound used against Zr-75-1 for IC50 is in the range of 8 to 15 μm, at an exposure period of at least 48 hrs.