# US 2010/0166884 A1 · Potentiation of cancer chemotherapy by 7-(2, 5- dihydro- 4-imidazo [1, 2-a] pyridine-3-yl-2,5-dioxo-ih-pyrrol-3-yl)-9-fluoro-1,2,3,4 tetrahydro -2-(1-piperidinyl-carbonyl)-pyrrolo [3,2,1-jk] [1,4] benzodiazepine

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- Number: US 2010/0166884 A1
- Document ID: US20100166884A1
- Status: Published application
- Kind: A1
- Application number: 12/664,664
- Filed: 2008-06-20
- Published: 2010-07-01
- Earliest claimed: 2007-07-02
- Assignees: Eli Lilly and Company
- Inventors: Aktham Aburub; Marcio Chedid; Thomas Albert Engler; Venkatraghavan Vasudevan
- Web page: https://patentgrep.com/patent/US20100166884A1

## CPC

- A61K 31/724: Cyclodextrins
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K 31/5517: condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
- A61K 31/555: containing heavy metals, e.g. hemin, hematin, melarsoprol
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 33/243: Platinum; Compounds thereof
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A method for treating gastric cancer, ovarian cancer, non-small cell lung cancer, or colorectal cancer in a patient is described, as well as pharmaceutical compositions comprising 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-IH-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinyl-carbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine, useful for the method and a process for preparing said compositions.

## Claims

### Claim 1

A method of treating ovarian cancer, non-small cell lung cancer, or colorectal cancer comprising administering to a cancer patient in need of such treatment an effective amount of a chemotherapeutic agent selected from the group consisting of CPT-11, pemetrexed, gemcitabine, etoposide, doxorubicin, and platinum chemotherapeutic agents in combination with an effective amount of 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinylcarbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine or a pharmaceutically acceptable salt or a solvate thereof.

### Claim 2

An improved method of using CPT-11, pemetrexed, gemcitabine, etoposide, doxorubicin, or a platinum chemotherapeutic agent in the treatment of ovarian cancer, non-small cell lung cancer, or colorectal cancer in a patient in need of such treatment, where the improvement comprises the co-administration of 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinyl-carbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine or a pharmaceutically acceptable salt or a solvate thereof.

### Claim 3 (depends on 1)

A method of claim 1 where the chemotherapeutic agent is a platinum chemotherapeutic agent.

### Claim 4 (depends on 3)

A method of claim 3 where the platinum chemotherapeutic agent is cisplatin or carboplatin.

### Claim at position 5

5-7. (canceled)

### Claim 8

A method of treating gastric cancer comprising administering to a cancer patient in need of such treatment an effective amount of a chemotherapeutic agent selected from the group consisting of 5-fluorouracil and platinum chemotherapeutic agents in combination with an effective amount of 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinylcarbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine or a pharmaceutically acceptable salt or a solvate thereof.

### Claim 9

An improved method of using 5-fluorouracil or a platinum chemotherapeutic agent in the treatment of gastric cancer in a patient in need of such treatment, where the improvement comprises the co-administration of 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinyl-carbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine or a pharmaceutically acceptable salt or a solvate thereof.

### Claim 10

(canceled)

### Claim 11

A pharmaceutical composition obtained by the steps comprising:
a) adding 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinyl-carbonyl)pyrrolo[3,2,1-jk][1,4]benzodiazepine or a pharmaceutically acceptable salt or a solvate thereof to an aqueous solution at a pH less than 5.5 containing at least 1 molar equivalent of SBE7-β-CD and optionally a pharmaceutically acceptable buffer;
b) adjusting the pH of the resulting solution to between 2.5 and 3.5 with a pharmaceutically acceptable acid or base; and
c) optionally lyophilizing the resulting solution.

### Claim 12

A pharmaceutical composition capable of reconstitution with water to a solution suitable for administration to a patient by injection or infusion, comprising one molar equivalent of 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinylcarbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine or a pharmaceutically acceptable salt or solvate thereof, at least one molar equivalent of SBE7-β-CD, and optionally a pharmaceutically acceptable buffer.

### Claim 13 (depends on 12)

A pharmaceutical composition of claim 12 wherein the pharmaceutically acceptable buffer is present.

### Claim 14 (depends on 13)

A pharmaceutical composition of claim 13 wherein the pharmaceutically acceptable buffer is tartaric acid.

### Claim 15

A pharmaceutical composition comprising one molar equivalent of 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinylcarbonyl)-pyrrolo[3,2,1-jk][1,4]benzo-diazepine and at least one molar equivalent of SBE7-β-CD.

### Claim 16

A process for the preparation of a pharmaceutical composition comprising 7-2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinyl-carbonyl)pyrrolo-[3,2,1-jk][1,4]benzodiazepine that is capable of reconstitution with water to a solution suitable for administration to a patient by injection or infusion, comprising the steps of:
a) adding 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinyl-carbonyl)pyrrolo[3,2,1-jk][1,4]benzodiazepine or a pharmaceutically acceptable salt or a solvate thereof to an aqueous solution at a pH less than 5.5 containing at least 1 molar equivalent of SBE7-β-CD and optionally a pharmaceutically acceptable buffer;
b) adjusting the pH of the resulting solution to between 2.5 and 3.5 with a pharmaceutically acceptable acid or base; and
c) lyophilizing the resulting solution.

### Claim 17

A method of treating ovarian cancer, non-small cell lung cancer, or colorectal cancer comprising administering to a cancer patient in need of such treatment an effective amount of pemetrexed and a platinum chemotherapeutic agent in combination with an effective amount of 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinylcarbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine or a pharmaceutically acceptable salt or a solvate thereof.

### Claim 18 (depends on 17)

A method of claim 17 where the platinum chemotherapeutic agent is cisplatin or carboplatin.

### Claim 19

A method of treating gastric cancer comprising administering to a cancer patient in need of such treatment an effective amount of pemetrexed and a platinum chemotherapeutic agent in combination with an effective amount of 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinylcarbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine or a pharmaceutically acceptable salt or a solvate thereof.

### Claim 20 (depends on 19)

A method of claim 19 where the platinum chemotherapeutic agent is cisplatin or carboplatin.