# US 8,569,265 B2 · Deuterated analogs of (4S)-4-ethyl-4-hydroxy-11-[2- (trimethylsilyl)ethyl]-1H-pyrano[3′, 4′:6,7] indolizino [1,2-b]quinoline-3,14(4H, 12H)-dione and methods of use thereof

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- Number: US 8,569,265 B2
- Document ID: US8569265B2
- Status: Granted
- Kind: B2
- Application number: 13/068,244
- Filed: 2011-05-06
- Published: 2012-11-08
- Granted: 2013-10-29
- Earliest claimed: 2011-05-06
- Assignees: BioNumerik Pharmaceuticals, Inc.
- Applicants: Xinghai Chen; Qiuli Huang; Harry Kochat; Andrey Malakhov; Frederick H. Hausheer
- Inventors: Xinghai Chen; Qiuli Huang; Harry Kochat; Andrey Malakhov; Frederick H. Hausheer
- Web page: https://patentgrep.com/patent/US8569265B2

## CPC

- C07B 59/004: {Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium}
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- C07F 7/0812: {comprising a heterocyclic ring}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- 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)

## Abstract

The present invention discloses: (i) two novel deuterated Karenitecin® analogs, pharmaceutically-acceptable salts, and/or derivatives thereof; (ii) methods of synthesis of said novel deuterated Karenitecin® analogs, pharmaceutically-acceptable salts, and/or derivatives thereof; (iii) pharmaceutically-acceptable formulations comprising said novel deuterated Karenitecin® analogs, pharmaceutically-acceptable salts, derivatives thereof; and/or, optionally, one or more additional chemotherapeutic agents; and (iv) methods of administration of said novel deuterated Karenitecin® analogs, pharmaceutically-acceptable salts, derivatives thereof; and/or, optionally, one or more additional chemotherapeutic agents, to subjects in need thereof.

## Claims

### Claim 1

A deuterated analog of (4S)-4-Ethyl-4-hydroxy-11-[2-(trimethylsilyl)ethyl]-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione (also known as 7-[2-trimethylsilyl)ethyl]-20(S)-camptothecin; BNP1350; and Karenitecin), BNP10120 (4S)-12,12-Dideutero-4-ethyl-4-hydroxy-11-[2-(trimethylsilyl)ethyl]-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; wherein BNP10120 consists of the chemical structure illustrated below:
and
pharmaceutically-acceptable salts thereof.

### Claim 2

A deuterated analog of (4S)-4-Ethyl-4-hydroxy-11-[2-(trimethylsilyl)ethyl]-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione (also known as 7-[2-trimethylsilyl)ethyl]-20(S)-camptothecin; BNP1350; and Karenitecin), BNP10121 (S)-4-Ethyl-4-hydroxy-11-[1,1,2,2-tetradeutero-2-(trimethylsilyl)ethyl]-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; wherein BNP10121 consists of the chemical structure illustrated below:
and
pharmaceutically-acceptable salts thereof.

### Claim 3 (depends on 1, 2)

A deuterated Karenitecin analog of claim 1 or 2, wherein each of the positions represented in the chemical structures as “D” in said analogs have deuterium enrichment of at least 98%.

### Claim 4 (depends on 1, 2)

A deuterated Karenitecin analog of claim 1 or 2, wherein each of the positions represented in the chemical structures as “D” in said analogs have deuterium enrichment of at least 90%.

### Claim 5 (depends on 1, 2)

A deuterated Karenitecin analog of claim 1 or 2, wherein each of the positions represented in the chemical structures as “D” in said analogs have deuterium enrichment of at least 50%.

### Claim 6 (depends on 1, 2)

A deuterated Karenitecin analog of claim 1 or 2, wherein each of the positions represented in the chemical structures as “D” in said analogs have deuterium enrichment of at least 20%.

### Claim 7 (depends on 1, 2)

A deuterated Karenitecin analog of claim 1 or 2, wherein each of the positions represented in the chemical structures as “D” in said analogs have deuterium enrichment of at least 10%.

### Claim 8 (depends on 1, 2)

A deuterated Karenitecin analog of claim 1 or 2, wherein each of the positions represented in the chemical structures as “D” in said analogs have deuterium enrichment of at least 5%.

### Claim 9 (depends on 1, 2)

A deuterated Karenitecin analog of claim 1 or 2, wherein each of the positions in the chemical structures represented as “D” in said analogs have deuterium enrichment of at least 1%.

### Claim 10 (depends on 1, 2)

A formulation containing a deuterated Karenitecin analog of claim 1 or 2, to provide a total dose from approximately 0.1 mg/m2 to approximately 100 mg/m2 of said deuterated Karenitecin analog, for administration to a subject with ovarian cancer in need thereof.

### Claim 11 (depends on 1, 2)

A formulation containing a deuterated Karenitecin analog of claim 1 or 2, which is administered to a subject in with ovarian cancer need thereof with one or more chemotherapeutic agents.

### Claim 12 (depends on 1, 2)

A formulation containing a deuterated Karenitecin analog of claim 1 or 2, wherein said formulation is administered to a subject with ovarian cancer.