# US 11,078,203 B2 · Deuterated fezolinetant

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- Number: US 11,078,203 B2
- Document ID: US11078203B2
- Status: Granted
- Kind: B2
- Application number: 16/629,710
- Filed: 2018-07-12
- Published: 2020-08-27
- Granted: 2021-08-03
- Earliest claimed: 2017-07-12
- Assignees: Ogeda SA
- Applicants: Ogeda SA
- Inventors: Hamid Hoveyda
- Web page: https://patentgrep.com/patent/US11078203B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 5/08: for decreasing, blocking or antagonising the activity of the anterior pituitary hormones
- A61P 5/24: of the sex hormones
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

Deuterated fezolinetant (R)-(4-fluorophenyl)-(8-methyl-3-(3-(methyl-d3)-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]trizolo[4,3-a]pyrazin-7(8H)-yl)methanone: or a pharmaceutically acceptable salt or solvate thereof, as an NK-3 antagonist. Also, methods of modulating NK-3 receptor activity including administering an effective amount of the compound or pharmaceutically acceptable salt or solvate thereof. Additionally, a process for manufacturing the compound or pharmaceutically acceptable salt or solvate thereof.

## Claims

### Claim 1

(R)-(4-fluorophenyl)-(8-methyl-3-(3-(methyl-d3)-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]trizolol[4,3-a]pyrazin-7(8H)-yl)methanone or a pharmaceutically acceptable salt or solvate thereof.

### Claim 2 (depends on 1)

The (R)-(4-fluorophenyl)-(8-methyl-3-(3-(methyl-d3)-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]trizolo[4,3-a]pyrazin-7(8H)-yl)methanone or a pharmaceutically acceptable salt or solvate thereof according to claim 1, formulated in a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.

### Claim 3

A method for modulating NK-3 receptor activity in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of (R)-(4-fluorophenyl)-(8-methyl-3-(3-(methyl-d3)-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]trizolo[4,3-a]pyrazin-7(8H)-yl)methanone or a pharmaceutically acceptable salt or solvate thereof.

### Claim 4 (depends on 3)

The method according to claim 3, for treating a disease selected from depression, anxiety, psychosis, schizophrenia, psychotic disorders, bipolar disorders, cognitive disorders, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder (ADHD), pain, convulsion, obesity, inflammatory diseases including irritable bowel syndrome (IBS) and inflammatory bowel disorders, emesis, preeclampsia, airway related diseases including chronic obstructive pulmonary disease, asthma, airway hyperresponsiveness, bronchoconstriction and cough, urinary incontinence, reproduction disorders, contraception and sex hormone-dependent diseases, benign prostatic hyperplasia (BPH), prostatic hyperplasia, metastatic prostatic carcinoma, testicular cancer, breast cancer, ovarian cancer, androgen dependent acne, male pattern baldness, endometriosis, abnormal puberty, uterine fibrosis, uterine fibroid tumor, uterine leiomyoma, hormone-dependent cancers, hyperandrogenism, hirsutism, virilization, polycystic ovary syndrome (PCOS), premenstrual dysphoric disease (PMDD), HAIR-AN syndrome (hyperandrogenism, insulin resistance and acanthosis nigricans), ovarian hyperthecosis (HAIR-AN with hyperplasia of luteinized theca cells in ovarian stroma), other manifestations of high intraovarian androgen concentrations, follicular maturation arrest, atresia, anovulation, dysmenorrhea, dysfunctional uterine bleeding, infertility, androgen-producing tumor (virilizing ovarian tumor or virilizing adrenal tumor), menorrhagia and adenomyosis.

### Claim 5 (depends on 3)

The method according to claim 3, for treating hot flashes.

### Claim 6 (depends on 3)

The method according to claim 3, for lowering the circulating LH levels.

### Claim 7

A process of manufacturing (R)-(4-fluorophenyl)-(8-methyl-3-(3-(methyl-d3)-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]trizolo[4,3-a]pyrazin-7(8H)-yl)methanone or a pharmaceutically acceptable salt or solvate thereof, comprising the steps of:
a) reacting a compound of Formula (i)
wherein:
PG represents a suitable protecting group;
with a compound of Formula (ii)
so as to obtain a compound of Formula (iii)
wherein PG is as defined above;
b) deprotecting compound of Formula (iii) with a suitable deprotection agent to afford compound of Formula (iv)
c) N-acylating compound of Formula (iv), with a compound of Formula (v)
leading to (R)-(4-fluorophenyl)-(8-methyl-3-(3-(methyl-d3)-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]trizolo[4,3-a]pyrazin-7(8H)-yl)methanone.

### Claim 8 (depends on 7)

The process according to claim 7, wherein the protecting group PG is selected from 2,4-dimethoxybenzyl (DMB), 4-methoxybenzyl (PMB), tert-butoxycarbonyl (Boc), allyl, diphenyl-phosphiramide (DPP) and 2-trimethylsilylethanesulfonyl (SES).

### Claim 9 (depends on 7)

The process according to claim 7, wherein the protecting group PG is 2,4-dimethoxybenzyl (DMB).