# US 2019/0375751 A1 · Hydrochloride salts of 8-[{1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one and preparation process therefor

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- Number: US 2019/0375751 A1
- Document ID: US20190375751A1
- Status: Published application
- Kind: A1
- Application number: 16/243,404
- Filed: 2019-01-09
- Published: 2019-12-12
- Earliest claimed: 2006-04-05
- Assignees: OPKO Health, Inc.
- Applicants: OPKO Health, Inc.
- Inventors: Mengwei Hu; Sunil Paliwal; Neng-Yang Shih; Frank Bruno Guenter; Ingrid Mergelsberg
- Web page: https://patentgrep.com/patent/US20190375751A1

## CPC

- C07D 471/10: Spiro-condensed systems
- A61K 31/435: having six-membered rings with one nitrogen as the only ring hetero atom
- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/08: for nausea, cinetosis or vertigo; Antiemetics
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/06: Antimigraine agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Disclosed are hydrochloride and tosylate crystalline salt forms of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one, represented by Formula I and methods of preparing the same.

## Claims

### Claim at position 1

1-39. (canceled)

### Claim 40

A crystalline hydrochloride anhydrous Form I salt form of 8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one (Formula I),
characterized by an X-ray powder diffraction pattern having peaks present at diffraction angles (in 2θ±0.2) of: 12.9; 15.4; 17.3; and 20.2.

### Claim 41

A crystalline hydrochloride anhydrous Form II salt form of 8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one (Formula I),
characterized by an x-ray powder diffraction pattern having peaks present at diffraction angles (in 2θ±0.2) of: 7.0; 9.0; 12.6; and 20.2.

### Claim 42 (depends on 40)

A pharmaceutical composition comprising the crystalline salt form of claim 40 and a pharmaceutically acceptable carrier optionally in combination with one or more additional therapeutic agents.

### Claim 43 (depends on 41)

A pharmaceutical composition comprising the crystalline salt form of claim 41 and a pharmaceutically acceptable carrier optionally in combination with one or more additional therapeutic agents.

### Claim 44 (depends on 40)

A method of treating or delaying the onset of nausea and/or emesis in a mammal which comprises administering to said mammal the crystalline salt form of claim 40.

### Claim 45 (depends on 41)

A method of treating or delaying the onset of nausea and/or emesis in a mammal which comprises administering to said mammal the crystalline salt form of claim 41.

### Claim 46 (depends on 40)

A method of treating or delaying the onset of chemotherapy-induced nausea and/or chemotherapy induced emesis in a mammal receiving chemotherapy, which comprises administering to said mammal the crystalline salt form of claim 40.

### Claim 47 (depends on 46)

The method of claim 46 further comprising contemporaneous administration of a chemotherapeutic agent.

### Claim 48 (depends on 41)

A method of treating or delaying the onset of chemotherapy-induced nausea and/or chemotherapy induced emesis in a mammal receiving chemotherapy, which comprises administering to said mammal the crystalline salt form of claim 41.

### Claim 49 (depends on 48)

The method of claim 48 further comprising contemporaneous administration of a chemotherapeutic agent.

### Claim 50

A process for preparing a crystalline salt form of 8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one
comprising a step of treating Formula 1 with at least one equivalent of an acid selected from hydrochloric acid and 4-toluenesulfonic acid to provide the crystalline salt form of Formula 1.

### Claim 51 (depends on 50)

The process of claim 50, wherein the acid is hydrochloric acid.

### Claim 52 (depends on 50)

The process of claim 50, wherein the acid is 4-toluenesulfonic acid.

### Claim 53 (depends on 51)

The process of claim 51, further comprising a step of precipitating from a solvent a crystalline hydrochloride monohydrate form of Formula 1.

### Claim 54 (depends on 53)

The process of claim 53, wherein the solvent comprises ethanol and water.

### Claim 55 (depends on 54)

The process of claim 54, wherein the crystalline hydrochloride monohydrate form of Formula 1 is a Form I crystalline salt form of 8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one monohydrate hydrochloride.

### Claim 56 (depends on 55)

The process of claim 55, wherein the Form I crystalline salt form of 8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one monohydrate hydrochloride is characterized by an X-ray powder diffraction pattern having a diffraction angle (in 2θ) of 21.6±0.2.

### Claim 57 (depends on 52)

The process of claim 52, further comprising a step of precipitating from a first solvent a crystalline tosylate form of Formula 1.

### Claim 58 (depends on 57)

The process of claim 57, wherein the first solvent comprises ethanol and diethyl ether.

### Claim 59 (depends on 58)

The process of claim 58, wherein the crystalline tosylate form of Formula 1 is a Form I crystalline salt form of 8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one tosylate.