# US 9,750,740 B2 · Spirocyclic compounds as tryptophan hydroxylase inhibitors

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- Number: US 9,750,740 B2
- Document ID: US9750740B2
- Status: Granted
- Kind: B2
- Application number: 15/278,130
- Filed: 2016-09-28
- Published: 2017-04-06
- Granted: 2017-09-05
- Earliest claimed: 2013-09-06
- Assignees: Kanos Pharmaceuticals, Inc.
- Applicants: Karos Pharmaceuticals, Inc.
- Inventors: Stéphane De Lombaert; Daniel R. Goldberg; Kenneth Brameld; Eric Brian Sjogren
- Web page: https://patentgrep.com/patent/US9750740B2

## CPC

- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/0078: {for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/08: for nausea, cinetosis or vertigo; Antiemetics
- A61P 1/10: Laxatives
- A61P 1/12: Antidiarrhoeals
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 19/10: for osteoporosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 471/10: Spiro-condensed systems
- 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
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention is directed to spirocyclic compounds which are inhibitors of tryptophan hydroxylase (TPH), particularly isoform 1 (TPH1), that are useful in the treatment of diseases or disorders associated with peripheral serotonin including, for example, gastrointestinal, cardiovascular, pulmonary, inflammatory, metabolic, and low bone mass diseases, as well as serotonin syndrome, and cancer.

## Claims

### Claim 1

A pharmaceutical composition suitable for administration to a patient by inhalation comprising (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the composition is in the form of a powder.

### Claim 3 (depends on 1)

The composition of claim 1, wherein the composition is administered as a spray or aerosol.

### Claim 4 (depends on 3)

The composition of claim 3, wherein the aerosol is administered by a sonic nebulizer.

### Claim 5 (depends on 1)

A method of lowering peripheral serotonin in a patient comprising administering by inhalation to said patient a composition of claim 1.

### Claim 6 (depends on 1)

A method of treating pulmonary arterial hypertension (PAH) in a patient, comprising administering by inhalation to said patient a therapeutically effective amount of a composition of claim 1.

### Claim 7 (depends on 6)

The method of claim 6 wherein said PAH is associated pulmonary arterial hypertension (APAH).

### Claim 8

A pharmaceutical composition suitable for administration to a patient by injection or infusion comprising (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

### Claim 9 (depends on 8)

The composition of claim 8, wherein the injection is subcutaneous, intravenous, or intramuscular.

### Claim 10 (depends on 8)

The composition of claim 8, wherein the composition is suitable for administration to a patient by infusion.

### Claim 11 (depends on 8)

The composition of claim 8, wherein the composition comprises one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions.

### Claim 12 (depends on 8)

A method of lowering peripheral serotonin in a patient comprising administering by injection or infusion to said patient a composition of claim 8.

### Claim 13 (depends on 8)

A method of treating pulmonary arterial hypertension (PAH) in a patient, comprising administering by injection or infusion to said patient a therapeutically effective amount of a composition of claim 8.

### Claim 14 (depends on 13)

The method of claim 13 wherein said PAH is associated pulmonary arterial hypertension (APAH).

### Claim 15

A pharmaceutical composition suitable for topical administration to a patient comprising (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

### Claim 16 (depends on 15)

The composition of claim 15, wherein the composition is administered in the form of a powder, spray, ointment, paste, cream, lotion, gel, solution, or patch.

### Claim 17 (depends on 15)

A method of lowering peripheral serotonin in a patient comprising topically administering to said patient a composition of claim 15.

### Claim 18 (depends on 15)

A method of treating pulmonary arterial hypertension (PAH) in a patient, comprising topically administering to said patient a therapeutically effective amount of a composition of claim 15.

### Claim 19 (depends on 18)

The method of claim 18 wherein said PAH is associated pulmonary arterial hypertension (APAH).

### Claim 20

A pharmaceutical composition suitable for oral administration to a patient comprising (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

### Claim 21 (depends on 20)

The composition of claim 20, wherein the composition is prepared in the form of a capsule, a tablet, a pill, a dragee, a powder, or granules.

### Claim 22 (depends on 20)

A method of lowering peripheral serotonin in a patient comprising orally administering to said patient a composition of claim 20.

### Claim 23 (depends on 20)

A method of treating pulmonary arterial hypertension (PAH) in a patient, comprising orally administering to said patient a therapeutically effective amount of a composition of claim 20.

### Claim 24 (depends on 23)

The method of claim 23 wherein said PAH is associated pulmonary arterial hypertension (APAH).

### Claim 25

A method of treating pulmonary arterial hypertension (PAH) in a patient, comprising administering to said patient a therapeutically effective amount of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate, or a pharmaceutically acceptable salt thereof.

### Claim 26 (depends on 25)

The method of claim 25 wherein said PAH is associated pulmonary arterial hypertension (APAH).