# US 9,751,875 B2 · Quinine compounds, and optical isomers, preparation method and medical use thereof

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- Number: US 9,751,875 B2
- Document ID: US9751875B2
- Status: Granted
- Kind: B2
- Application number: 14/904,766
- Filed: 2014-07-11
- Published: 2016-08-25
- Granted: 2017-09-05
- Earliest claimed: 2013-07-13
- Assignees: Beijing Fswelcome Technology Development Co., Ltd.
- Applicants: Beijing Fswelcome Technology Development Co., Ltd.
- Inventors: Chunjing Wang; Junyi Wang; Zejun Gao
- Web page: https://patentgrep.com/patent/US9751875B2

## CPC

- C07D 453/02: containing not further condensed quinuclidine ring systems
- A61K 9/0043: {Nose}
- A61K 9/007: {Pulmonary tract; Aromatherapy}
- A61K 9/008: {comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]}
- A61K 9/20: Pills, tablets, {discs, rods (A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095)}
- A61K 9/4808: {characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release (capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084)}
- A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone}
- A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- 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 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 11/14: Antitussive agents
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 13/10: of the bladder
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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

The present invention discloses a class of quinine compounds and pharmaceutically acceptable salts, solvates, prodrugs or optical isomers thereof. Also disclosed in the present invention are that the above compounds have a selective antagonistic effect on the receptor subtypes of M1 and M3, but have no significant effect on M2 receptor subtype, and the above compounds are characterized by rapid action, long-lasting efficacy, and low toxic and side-effects when used to treat rhinitis, post-cold rhinitis, chronic trachitis, airway hyperresponsiveness, asthma, chronic obstructive pulmonary diseases, cough, urinary incontinence, frequent urination, unstable bladder syndrome, bladder spasms, bladder inflammation and gastrointestinal diseases such as irritable bowel syndrome, spastic colitis, as well as duodenal and gastric ulcers.

## Claims

### Claim 1

A compound of formula I:
or a pharmaceutically acceptable salt, solvate or optical isomer thereof,
wherein in formula I:
n is from 1-7,
R1 is a C3-C7 hydrocarbyl which can be unsubstituted or optionally substituted by halogen, alkoxy, alkoxyhydrocarbyl, heterocyclyl or aryl,
R2 is an aryl or a heteroaryl containing one or more heteroatoms which can be unsubstituted, or optionally substituted,
R3 is a hydroxyl, halogen, alkoxy or acyloxy, wherein the alkoxy or acyloxy can be unsubstituted or optionally substituted by halogen, hydroxyl, alkoxy, hydrocarbyl, alkoxyhydrocarbyl, heterocyclyl, or aryl;
R4 and R5 can be present or absent, and are independently selected from the group consisting of halogen, hydroxyl, alkoxy, hydrocarbyl, alkoxyhydrocarbyl, heterocyclyl or aryl, when present;
Y is a linear or branched C1-C7 alkyl or —(CH2—O—CH2)m—, which can be optionally substituted, wherein m is equal to 1-3,
X− is an acid radical or hydroxyl.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein:
n is 1-3, R1 is an unsubstituted cycloalkyl,
R2 is a phenyl, naphthyl, or biphenyl, which can be unsubstituted or optionally substituted by one or more of halogen, hydroxyl, phenyl, —OR6, —SR6, —NR6R7, —NHCOR6, —CONR6R7, —CN,—NO2, —COOR6, —CF3 or linear or branched C1-C4 hydrocarbyl, R6 and R7 can be a hydrogen atom, a linear or branched C1-C4 hydrocarbyl, or can form a cyclohydrocarbyl together,
R3 is a hydroxyl or methoxyl,
Y is a methyl, ethyl, propyl or —(CH2—O—CH2)2—.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein,
n is 1,
R1 is a cyclopentyl or cyclohexyl,
R2 is an unsubstituted phenyl, pyridyl, furyl or thienyl,
Y is an ethyl or propyl.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein X− is hydroxide or an acid radical of a pharmaceutically acceptable inorganic acid being selected from the group consisting of hydrochloric acid, bromic acid, iodic acid, nitric acid, carbonic acid, phosphoric acid, sulfuric acid or phosphorous acid , so that the compound of formula I is in the form of a quaternary ammonium base or a pharmaceutically acceptable salt being selected from the group consisting of hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrophosphate, dihydric phosphate, sulfate, disulfate or phosphite.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein X− is an acid radical of a pharmaceutically acceptable organic acid, so that the compound of formula I is in the form of a salt of an organic acid, wherein said organic acid is acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, glucuronic acid, galactonic acid or amino acid.

### Claim 6 (depends on 1)

The compound according to claim 1, which is:
(2S,3R)-3-[(2-cyclopentyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2S,3S)-3-[(2-cyclopentyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2R,3R)-3-[(2-cyclopentyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2R,3S)-3-[(2-cyclopentyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2S,3R),(2R,3S)-3-[(2-cyclopentyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2R,3R),(2S,3S)-3-[(2-cyclopentyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2S,3R)-3-[(2-cyclohexyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2S,3S)-3-[(2-cyclohexyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2R,3R)-3-[(2-cyclohexyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2R,3S)-3-[(2-cyclohexyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2R,3S),(2S,3R)-3-[(2-cyclohexyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2R,3R),(2S,3S)-3-[(2-cyclohexyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2S,3R)-3-[(2-cyclobutyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2S,3S)-3-[(2-cyclobutyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2R,3S)-3-[(2-cyclobutyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2R,3R)-3-[(2-cyclobutyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2R,3S),(2S,3R)-3-[(2-cyclobutyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2R,3R),(2S,3S)-3-[(2-cyclobutyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2S,3R)-3-[(2-cyclopropyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2R,3S)-3-[(2-cyclopropyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2S,3S)-3-[(2-cyclopropyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2R,3R)-3-[(2-cyclopropyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2R,3S),(2S,3R)-3-[(2-cyclopropyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2R,3R),(2S,3S)-3-[(2-cyclopropyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2S,3R)-3-[(2-cyclopentyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(2-phenoxyethyl)-1-azabicyclo[2,2,2]octane bromide;
(2R,3R)-3-[(2-cyclopentyl-2-hydroxyl-2-phenyl)ethoxyl]-1-(2-phenoxyethyl)-1-azabicyclo[2,2,2]octane bromide;
(2R,3R)-3-[(2-cyclopentyl-2-hydroxyl-2-phenyl)ethoxyl]-1-phenoxymethyl-1-azabicyclo[2,2,2]octane bromide;
(2R,3R)-3-[(2-cyclopentyl-2-hydroxyl-2-phenyl)ethoxyl]-1-phenoxymethoxymethyl-1-azabicyclo[2,2,2]octane chloride;
(2R 3R)-3-[(2-cyclopentyl-2-hydroxyl-2-naphthyl)ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2R,3R)-3-[(2-cyclopentyl-2-hydroxyl-2-(o-chlorophenyl))ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2R,3R)-3-[(2-cyclopentyl-2-hydroxyl-2-(3-pyridyl))ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide;
(2R,3R)-3-[(2-cyclopentyl-2-hydroxyl-2-(2-furyl))ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide; or (2R,3R)-3-[(2-cyclopentyl-2-methoxyl-2-(3-pyridyl))ethoxyl]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octane bromide.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier, wherein the composition can be any suitable dosage form; and the composition can further comprise or not comprise one or more of other drugs available for combined administration.

### Claim 8 (depends on 1)

A method for the manufacture of the compound according to claim 1 comprising the steps of:
(1) reacting R2—CN with R1—Br to form
and
reacting
with NaH, dimethyl sulfide and dimethyl sulfate to form an intermediate 1 being formula
(2) reacting the intermediate 1 with
in the presence of NaH to form an intermediate 2 being formula
(3) reacting
in the presence of NaOH to form an intermediate 4 being formula
wherein Z is halogen atom,
(4) reacting the intermediate 2 with the intermediate 4, to obtain the compound of formula (I).

### Claim 9 (depends on 8)

The method according to claim 8, further comprising the step of purifying and separating the chemical isomers of intermediate 2 after the completion of step (2).

### Claim 10 (depends on 8)

The method according to claim 8, wherein after the completion of step (4), the compound is reacted with Ag2O to replace halogen with hydroxide, which can be then converted into other acid radical by reacting with other acid.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1 for treating diseases associated with M receptors.

### Claim 12 (depends on 11)

The pharmaceutical composition of claim 11, wherein the diseases associated with M receptors are selected from the group consisting of rhinitis, post-cold rhinitis, chronic trachitis, airway hyperresponsiveness, asthma, chronic obstructive pulmonary diseases, cough, urinary incontinence, frequent urination, unstable bladder syndrome, bladder spasms, bladder inflammation, gastrointestinal diseases, irritable bowel syndrome, spastic colitis, duodenal ulcers, and gastric ulcers.

### Claim 13 (depends on 2)

The compound according to claim 2, wherein,
n is 1,
R1 is a cyclopentyl or cyclohexyl,
R2 is an unsubstituted phenyl, pyridyl, furyl or thienyl,
Y is an ethyl or propyl.

### Claim 14 (depends on 2)

A pharmaceutical composition comprising the compound according to claim 2 and a pharmaceutically acceptable carrier, wherein the composition can be any suitable dosage form; and the composition can further comprise or not comprise one or more of other drugs available for combined administration.

### Claim 15 (depends on 3)

A pharmaceutical composition comprising the compound according to claim 3 and a pharmaceutically acceptable carrier, wherein the composition can be any suitable dosage form; and the composition can further comprise or not comprise one or more of other drugs available for combined administration.

### Claim 16 (depends on 4)

A pharmaceutical composition comprising the compound according to claim 4 and a pharmaceutically acceptable carrier, wherein the composition can be any suitable dosage form; and the composition can further comprise or not comprise one or more of other drugs available for combined administration.

### Claim 17 (depends on 9)

The method according to claim 9, wherein after the completion of step (4), the compound is reacted with Ag2O to replace halogen with hydroxide, which can be then converted into other acid radical by reacting with other acid.

### Claim 18 (depends on 2)

A pharmaceutical composition comprising the compound of claim 2 for treating diseases associated with M receptors.

### Claim 19 (depends on 3)

A pharmaceutical composition comprising the compound of claim 3 for treating diseases associated with M receptors.

### Claim 20 (depends on 4)

A pharmaceutical composition comprising the compound of claim 4 for treating diseases associated with M receptors.

### Claim 21 (depends on 1)

A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier, wherein the composition can be the dosage form for inhalation administration or nasal administration; and the composition can further comprise or not comprise one or more of other drugs available for combined administration.

### Claim 22 (depends on 2)

A pharmaceutical composition comprising the compound according to claim 2 and a pharmaceutically acceptable carrier, wherein the composition can be the dosage form for inhalation administration or nasal administration; and the composition can further comprise or not comprise one or more of other drugs available for combined administration.

### Claim 23 (depends on 3)

A pharmaceutical composition comprising the compound according to claim 3 and a pharmaceutically acceptable carrier, wherein the composition can be the dosage form for inhalation administration or nasal administration; and the composition can further comprise or not comprise one or more of other drugs available for combined administration.

### Claim 24 (depends on 4)

A pharmaceutical composition comprising the compound according to claim 4 and a pharmaceutically acceptable carrier, wherein the composition can be the dosage form for inhalation administration or nasal administration; and the composition can further comprise or not comprise one or more of other drugs available for combined administration.