# US 8,772,314 B2 · Glycine derivatives and medicinal compositions thereof

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- Number: US 8,772,314 B2
- Document ID: US8772314B2
- Status: Granted
- Kind: B2
- Application number: 13/303,413
- Filed: 2011-11-23
- Published: 2012-05-31
- Granted: 2014-07-08
- Earliest claimed: 2010-11-26
- Assignees: Chiesi Farmaceutici S.p.A.
- Applicants: Gabriele Amari; Mauro Riccaboni; Marco Farina
- Inventors: Gabriele Amari; Mauro Riccaboni; Marco Farina
- Web page: https://patentgrep.com/patent/US8772314B2

## CPC

- C07D 207/12: Oxygen or sulfur atoms
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 11/08: Bronchodilators
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 29/02: without antiinflammatory effect
- C07D 451/10: acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
- C07D 453/02: containing not further condensed quinuclidine ring systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Alkaloid aminoester derivatives according to formula (I) and (VI) act as muscarinic receptor antagonists.

## Claims

### Claim 1

A compound of formula (I):
wherein:
R1 is —H, or linear or branched (C1-C10)alkyl, (C2-C6)alkenyl, aryl, (C3-C8)cycloalkyl, (C5-C10)heterocycloalkyl, aryl(C1-C6)alkyl, or heteroaryl, each of which may be optionally substituted by one or more substituents selected from the group consisting of a halogen atom, —OH, oxo (═O), —SH, —NO2, —N(R5)(R8), —CN, —CON(R5)2, —NHCO(R5), —COR5, —CO2R5, (C1-C10)alkylsulfanyl, (C1-C10)alkylsulfinyl, (C1-C10)alkylsulfonyl, (C1-C10)alkyl, (C1-C10)alkylcarboxyl, (C1-C10)alkoxy, aryl, aryloxy, and heteroaryl;
G is —OC(O)—, —SO2—, or —C(O)—;
R2 is —H or (C1-C10)alkyl or aryl(C1-C6)alkyl, each of which may be optionally substituted by one or more substituents selected from the group consisting of a halogen atom, —OH, oxo (═O), —SH, —NO2, —N(R5)2, —CN, —CON(R5)2, —NHCO(R5), —CO(R5), —CO2(R5), (C1-C10)alkylsulfanyl, (C1-C10)alkylsulfinyl, (C1-C10)alkylsulfonyl, (C1-C10)alkyl, (C1-C10)alkylcarboxyl, (C1-C10)alkoxy, aryl, aryloxy, and heteroaryl;
R3 is —H or (C1-C10)alkyl, aryl, (C3-C8)cycloalkyl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl, each of which may be optionally substituted by one or more substituents selected from the group consisting of a halogen atom, —OH, oxo (═O), —SH, —NO2, —N(R5)2, —CN, —CON(R5)2, —NHCO(R5), —CO(R5), —CO2(R5), (C1-C10)alkylsulfanyl, (C1-C10)alkylsulfinyl, (C1-C10)alkylsulfonyl, (C1-C10)alkyl, (C1-C10)alkylcarboxyl, (C1-C10)alkoxy, aryl, aryloxy, aryl(C1-C10)alkylenoxy, and heteroaryl;
R6 is a group of formula (i):
wherein
A− is a physiologically acceptable anion;
R4 is a group of formula (Y):
—(CH2)p-P—(CH2)q-W (Y)
wherein
p is 0 or an integer from 1 to 4;
q is 0 or an integer from 1 to 4;
P is absent or is —O—, —S—, —SO—, —SO2—, —C(O)—, —N(R5)-, —CH═CH—, —N(R5)(SO2)—, —N(R5)(COO)—, —N(R5)(C(O))—, —S(O2)N(R5)-, —CO(O)N(R5)-, or —C(O)N(R5)-;
W is —H, or linear or branched (C1-C10)alkyl, (C2-C6)alkenyl, aryl, (C3-C8)cycloalkyl, (C5-C10)heterocycloalkyl, aryl(C1-C6)alkyl, or heteroaryl, each of which may be optionally substituted by one or more substituents selected from the group consisting of a halogen atom, —OH, oxo (═O), —SH, —NO2, —N(R5)2, —CN, —CON(R5)2, —NH(COR5), —CO(R5), —CO2(R5), (C1-C10)alkylsulfanyl, (C1-C10)alkylsulfinyl, (C1-C10)alkylsulfonyl, (C1-C10)alkyl, (C1-C10)alkylcarboxyl, (C1-C10)alkoxy, aryl, aryloxy, and heteroaryl;
R5 and R8 are each independently —H, or (C1-C10)alkyl, (C1-C10)alkoxy, (C2-C6)alkynyl, (C2-C6)alkenyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C10)alkyl, heteroaryl, (C1-C10)alkyl-heteroaryl, or aryl, each of which may be optionally substituted by one or more substituents selected from the group consisting of a halogen atom, —OH, oxo (═O), —SH, —NO2, —CN, —CONH2, (C1-C10)alkylsulfanyl, (C1-C10)alkylsulfinyl, (C1-C10)alkylsulfonyl, (C1-C10)alkyl, (C1-C10)alkylcarboxyl, (C1-C10)alkoxy, aryl, aryloxy, and heteroaryl;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound or salt according to claim 1, wherein G is selected from the group consisting of —OC(O)—, —SO2—, and —C(O)—, R1 is selected from the group consisting of linear or branched (C1-C10)alkyl, aryl, (C3-C8)cycloalkyl, aryl(C1-C6)alkyl, (C2-C6)alkenyl, (C5-C10)heterocycloalkyl, and heteroaryl, each of which may be optionally substituted by one or more substituents selected from a halogen atom, —N(R5)(R8), (C1-C10)alkyl, (C1-C10)alkylcarboxyl, (C1-C10)alkoxy, aryloxy, and heteroaryl, and R2 is H.

### Claim 3 (depends on 2)

A compound or salt according to claim 2, wherein R1 is selected from the group consisting of methyl, ethyl, methoxyethoxyl, tert-butyl, ethenyl, cyclohexyl, phenyl, methoxyphenyl, chlorophenyl, difluorophenyl, dimethylthiazole, trifluoroethyl, phenylethyl, cyclopentyl, methylethoxyl, oxo-phenylethyl, thiophenyl, thiazolyl, fluorophenyl, amino-phenyl, tert-butoxycarbonylamino-phenyl, and methylphenyl.

### Claim 4 (depends on 1)

A compound or salt according to claim 1, wherein R3 is selected from the group consisting of (C1-C10)alkyl, aryl, and heteroaryl, each of which may be optionally substituted by one or more groups selected from a halogen atom, (C1-C10)alkyl, (C1-C10)alkoxy, and aryl(C1-C10)alkylenoxy.

### Claim 5 (depends on 1)

A compound or salt according to claim 1, wherein R6 is a residue of formula (i), R4 is a group of formula (Y) wherein p is 0, 1, and 3, P is CO, q is 0, and W is selected from the group consisting of (C1-C10)alkyl, aryl, heteroaryl, and (C5-C10)heterocycloalkyl, each of which may be optionally substituted by one or more substituents selected from the group consisting of a halogen atom, (C1-C10)alkyl, (C1-C10)alkoxy, —OH, and (C1-C10)alkylcarboxyl.

### Claim 6 (depends on 5)

A compound or salt according to claim 5, wherein W is selected from the group consisting of phenyl, benzothioxol, thiophenyl and thiazolyl, each of which may be optionally substituted by one or more substituents selected from the group consisting of a halogen atom, —OH, methyl, and methylcarboxyl.

### Claim 7 (depends on 1)

A pharmaceutical composition, comprising a compound or salt according to claim 1 and one or more pharmaceutically acceptable carriers and/or excipients.

### Claim 8 (depends on 1)

A combination of a compound or salt according to claim 1 and one or more active ingredients selected from the group consisting of a beta2-agonist, a corticosteroid, a P38 MAP kinase inhibitor, a IKK2 inhibitor, a HNE inhibitor, a PDE4 inhibitor, a leukotriene modulator, a NSAID, and a mucus regulator.

### Claim 9 (depends on 7)

A pharmaceutical composition according to claim 7, which is in a form suitable to be administered by inhalation.

### Claim 10 (depends on 9)

A pharmaceutical composition according to claim 9, which is an inhalable powder, a propellant-containing metering aerosol, or a propellant-free inhalable formulation.

### Claim 11 (depends on 9)

A device, which comprises a pharmaceutical composition according to claim 9.

### Claim 12 (depends on 11)

A device according to claim 11, which is a single-dose dry powder inhaler, a multi-dose dry powder inhaler, a metered dose inhaler, or a soft mist nebulizer.