# US 10,865,194 B2 · Therapeutically active bicyclic-sulphonamides and pharmaceutical compositions

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- Number: US 10,865,194 B2
- Document ID: US10865194B2
- Status: Granted
- Kind: B2
- Application number: 15/803,362
- Filed: 2017-11-03
- Published: 2019-05-09
- Granted: 2020-12-15
- Earliest claimed: 2017-11-03
- Assignees: Fondazione Istituto Italiano Di Tecnologia
- Applicants: Fondazione Istituto Italiano Di Tecnologia
- Inventors: Fabio Bertozzi; Tiziano Bandiera; Silvia Pontis; Angelo Reggiani; Francesca Giacomina; Paolo Di Fruscia
- Web page: https://patentgrep.com/patent/US10865194B2

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61K 31/4523: containing further heterocyclic ring systems
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 401/14: containing three or more hetero rings
- 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

## Abstract

Pharmaceutical compounds are disclosed having a bicyclic-sulphonamide structure of Formula 1: wherein R1 represents an unsubstituted or a substituted heteroaryl ring; R2, R3, R4, and R5 are independently selected from hydrogen, alkyl, hydroxyalkyl, and alkyl-O-alkyl, provided that either R2 and R3, or R4 and R5 are linked or taken together to form a bridge between the carbon atoms to which R2 and R3, or R4 and R5 respectively are directly linked, whereby the N-containing ring in Formula 1 is an azabicyclo moiety. The compounds and compositions including the compounds may be used in therapy as brain-cell-death protectants, for example, in the treatment of chronic neurodegenerative diseases. The compounds are active as inhibitors of N-acylethanolamine-hydrolysing acid amidase (NAAA) and may be used for the therapeutic treatment and prevention of pain and inflammatory disorders and other disorders which benefit from the modulation of fatty acid ethanolamides, particularly palmitoylethanolamide (PEA).

## Claims

### Claim 1

A compound having the structure of Formula I,
wherein:
R1 represents an unsubstituted or a substituted pyrazolyl or isoxazolyl ring;
R2, R3, R4 and R5 are independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl and alkyl-O-alkyl;
provided that either R2 and R3 or R4 and R5 are linked or taken together to form a bridge between the carbon atoms to which R2 and R3 or R4 and R5 respectively are directly linked wherein the heterocyclic N-containing ring shown in Formula I has a meaning selected from the group consisting of:
wherein Z is selected from CRviRvii, O, or can be absent;
Rii, Riii, Riv and Rv are independently selected from the group consisting of hydrogen and alkyl;
Rvi and Rvii are independently selected from the group consisting of hydrogen and alkyl;
R6 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cyano and halogen;
X is selected from the group consisting of O, S and NRx;
RX is independently selected from the group consisting of hydrogen and alkyl;
R7 is selected from the group consisting of phenyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,3-benzoxazolyl, quinolinyl, and quinoxalinyl;
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or racemic mixture thereof.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein R1 is a pyrazolyl, which is unsubstituted or mono- or bi-substituted with C1-C6alkyl, halo C1-C6alkyl, C3-C6cycloalkyl, aryl, heteroaryl, CORxi, COORxi, heterocycloalkyl, CONHRxi, CONRxiRxii, OH, O—C1-C6alkyl, O—C3-C6cycloalkyl, O-heterocycloalkyl, O-heteroaryl, O-aryl, O-halo C1-C6alkyl, C1-C6alkyl—O—C1-C6alkyl, C1-C6alkyl—O—C3-C6cycloalkyl, C1-C6alkyl-O-heterocycloalkyl, C1-C6alkyl-O-aryl, CN, NO2, NRxiii(Rxii)CORxiiiN(Rxii)COORxiv, N(Rxii)CONRxiiiRxiv, N(Rxii)SORxiii, SORxiii, halogen and hydroxy-C1-C6alkyl;
Rxi is selected from the group consisting of hydrogen, C1-C6alkyl, aryl, heteroaryl;
Rxii is selected from the group consisting of hydrogen, C1-C6alkyl;
Rxiii is selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cycloalkyl, aryl, heteroaryl and hydroxy-C1-C6alkyl;
Rxiv is selected from the group consisting of hydrogen, C1-C6alkyl.

### Claim 3 (depends on 1)

A compound according to claim 1 wherein R1 is selected from the group consisting of pyrazolyl, and isoxazolyl, unsubstituted or mono- or bi-sub stituted with C1-C6alkyl, haloC1-C6alkyl, C3-C6cycloalkyl, aryl, OH, O—C1-C6alkyl, O-halo C1-C6alkyl, CN, NO2 and halogen.

### Claim 4 (depends on 1)

A compound according to claim 1, wherein X is oxygen.

### Claim 5 (depends on 1)

A compound according to claim 1 wherein R6 is hydrogen or C1-C4alkyl.

### Claim 6 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutical acceptable carrier, excipient or diluent.

### Claim 7 (depends on 1)

A compound according to claim 1, selected from the group consisting of:
(1R,3s,5S)-8-[(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-3-phenoxy-8-azabicyclo[3.2.1]octane,
(1R,3r,5 S)-8-[(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-3-phenoxy-8-azabicyclo[3.2.1]octane,
(1R,3s,5 S)-8-[(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-3-pyridazin-3-yloxy-8-azabicyclo[3.2.1]octane,
(1R,3r,5 S)-9-[(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-3-(pyrazin-2-yloxy)-9-azabicyclo[3.3.1]nonane,
(1R,3 s,5 S)-9-[(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-3-(pyrazin-2-yloxy)-9-azabicyclo[3.3.1]nonane,
(1R,3s,5 S)-9-[(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-7-pyrazin-2-yloxy-3-oxa-9-azabicyclo[3.3.1]nonane,
(1R,3r,5 S)-9-[(3, 5-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-7-pyrazin-2-yloxy-3-oxa-9-azabicyclo[3.3.1]nonane,
(1R,5S,9r)-7-(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)-9-(pyrazin-2-yloxy)-3-oxa-7-azabicyclo[3.3.1]nonane,
(1R,5S,9s)-7-(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)-9-(pyrazin-2-yloxy)-3-oxa-7-azabicyclo[3.3.1]nonane,
(1R,5S,8r)-3-(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)-8-(pyrazin-2-yloxy)-3-azabicyclo[3.2.1]octane,
(1R,5S,9r)-3-(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)-9-(pyrazin-2-yloxy)-3-azabicyclo[3.3.1]nonane, and
(1R,5S,9s)-3-(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)-9-(pyrazin-2-yloxy)-3-azabicyclo[3.3.1]nonane.