# US 8,772,298 B2 · Spirocyclic heterocycles medicaments containing said compounds, use thereof and method for their production

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- Number: US 8,772,298 B2
- Document ID: US8772298B2
- Status: Granted
- Kind: B2
- Application number: 13/920,389
- Filed: 2013-06-18
- Published: 2013-10-24
- Granted: 2014-07-08
- Earliest claimed: 2008-02-07
- Assignees: Boehringer Ingelheim International GmbH
- Applicants: Frank Himmelsbach; Birgit Jung; Ralf Lotz
- Inventors: Frank Himmelsbach; Birgit Jung; Ralf Lotz
- Web page: https://patentgrep.com/patent/US8772298B2

## CPC

- C07D 403/12: linked by a chain containing hetero atoms as chain links
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 11/08: Bronchodilators
- A61P 11/10: Expectorants
- A61P 11/14: Antitussive agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- 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: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to spirocyclic heterocycles of general formula (I) the tautomers, the stereoisomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids, which have valuable pharmacological properties, particularly an inhibitory effect on signal transduction mediated by tyrosine kinases, the use thereof for the treatment of diseases, particularly tumoral diseases as well as benign prostatic hyperplasia (BPH), diseases of the lungs and airways, and the preparation thereof.

## Claims

### Claim 1

A method for the treatment of a disease of the airways accompanied by increased production of mucus, wherein the disease is selected from chronic bronchitis, chronic obstructive bronchitis (COPD), asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, α1-antitrypsin deficiency, coughs, pulmonary emphysema, pulmonary fibrosis and hyperreactive airways, comprising administering to a patient a therapeutically effective amount of a compound of formula (I)
wherein
Ra denotes a phenyl or 1-phenylethyl group, wherein the phenyl nucleus is substituted in each case by the groups R1 to R3, wherein
R1 and R2 which may be identical or different, denote hydrogen or
a group selected from among
F, Cl, Br, I, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3, CN, NO2, NH2 and OH,
or
a group selected from among
C1-4-alkyl, C1-4-alkyl-O, C2-3-alkenyl, C2-3-alkynyl,
phenyl, phenyl-O, phenyl-C1-3-alkyl, phenyl-C1-3-alkyl-O, heteroaryl, heteroaryl-O, heteroaryl-C1-3-alkyl, heteroaryl-C1-3-alkyl-O, while the above-mentioned phenyl groups are mono- or disubstituted by groups R5,
and
R3 denotes hydrogen,
or
a group selected from among
F, Cl, Br and CH3,
Rb denotes hydrogen, or a group, optionally substituted, selected from among C1-6-alkyl, C3-6-cycloalkyl- and C3-6-cycloalkyl-C1-3-alkyl,
Rc denotes hydrogen, or an optionally substituted group selected from among C1-6-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-3-alkyl, C1-6-alkyl-CO, C3-6-cycloalkyl-CO, C3-6-cycloalkyl-C1-3-alkyl-CO, C1-6-alkyl-SO2, C3-6-cycloalkyl-SO2, C3-6-cycloalkyl-C1-3-alkyl-SO2, phenyl-CO— and phenyl-SO2,
Rd denotes hydrogen or
a group selected from among
F, Cl, Br, I, OH, C1-4-alkyl, C1-4-alkyl-O, C1-2-alkyl-O substituted by 1 to 3 fluorine atoms, C3-7-cycloalkyl-O, C3-7-cycloalkyl-C1-4-alkyl-O, tetrahydrofuran-3-yl-O, tetrahydropyran-3-yl-O, tetrahydro-pyran-4-yl-O, tetrahydrofuranyl-C1-4-alkyl-O— and tetrahydropyranyl-C1-4-alkyl-O,
or
R4—C1-4-alkyl, while the linking of the groups R4 may take place via each C atom of the alkyl group,
or
R4—C2-4-alkyl-O, wherein the group R4 is separated from the oxygen atom by at least 2 C atoms,
or
a group selected from among
pyrrolidin-2-yl-C1-4-alkyl-O, pyrrolidin-3-yl-C1-4-alkyl-O, piperidin-2-yl-C1-4-alkyl-O, piperidin-3-yl-C1-4-alkyl-O, piperidin-4-yl-C1-4-alkyl-O, azepan-2-yl-C1-4-alkyl-O, azepan-3-yl-C1-4-alkyl-O, azepan-4-yl-C1-4-alkyl-O, morpholin-2-yl-C1-4-alkyl-O, morpholin-3-yl-C1-4-alkyl-O, 1-(C1-3-alkyl)-pyrrolidin-2-yl-C1-4-alkyl-O, 1-(C1-3-alkyl)-pyrrolidin-3-yl-C1-4-alkyl-O, 1-(C1-3-alkyl)-piperidin-2-yl-C1-4-alkyl-O, 1-(C1-3-alkyl)-piperidin-3-yl-C1-4-alkyl-O, 1-(C1-3-alkyl)-piperidin-4-yl-C1-4-alkyl-O, 1-(C1-3-alkyl)-azepan-2-yl-C1-4-alkyl-O, 1-(C1-3-alkyl)-azepan-3-yl-C1-4-alkyl-O, 1-(C1-3-alkyl)-azepan-4-yl-C1-4-alkyl-O, 4-(C1-3-alkyl)-morpholin-2-yl-C1-4-alkyl-O— and 4-(C1-3-alkyl)-morpholin-3-yl-C1-4-alkyl-O,
while
R4 denotes a group, which may be identical or different, selected from among OH, C1-3-alkyl-O, C3-6-cycloalkyl-O, NH2, C1-3-alkyl-NH, (C1-3-alkyl)2N, (2-methoxyethyl)2N, pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl, morpholin-4-yl, 1,4-oxazepan-4-yl, 2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl, 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl, piperazin-1-yl, 4-(C1-3-alkyl)-piperazin-1-yl, 1,4-diazepan-1-yl, 4-(C1-3-alkyl)-1,4-diazepan-1-yl, HCO—NH, C1-4-alkyl-CO—NH, C1-3-alkyl-O—C1-3-alkyl-CO—NH, C1-4-alkyl-O—CO—NH, H2NCONH, C1-3-alkyl-NH—CO—NH, (C1-3-alkyl)2N—CONH, pyrrolidin-1-yl-CO—NH, piperidin-1-yl-CO—NH , piperazin-1-yl-CO—NH, 4-(C1-3-alkyl)-piperazin-1-yl-CO—NH , morpholin-4-yl-CO—NH— and C1-4-alkyl-SO2—NH,
while the pyrrolidinyl, piperidinyl, azepan-1-yl, piperazinyl, 1,4-diazepan-1-yl, morpholinyl- and 1,4-oxazepan-4-yl groups mentioned above in the definition of the group Rd may each additionally be substituted by one or two C1-3-alkyl groups,
and
wherein the above-mentioned phenyl groups are mono- or disubstituted by groups R5, wherein
R5 denotes hydrogen, or
a group, which may be identical or different, selected from among
F, Cl, Br, I, OH, CN, C1-3-alkyl, C1-3-alkyl-O, CHF2, CF3, —O—CHF2 and —O—CF3,
and
unless stated otherwise, the above-mentioned alkyl groups may be straight-chain or branched,
A denotes a C2-alkylene group
wherein the C2-alkylene group may be 1-, 2-, 3- or 4-substituted by a group R6,
and
R6 which may be identical or different, denotes hydrogen, or
a group selected from among OH, C1-C4-alkyl and —O—C1-C4-alkyl
optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, or a pharmacologically acceptable acid addition salt thereof.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the disease is chronic obstructive bronchitis (COPD) or asthma.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the compound of formula (I) is
or a pharmacologically acceptable acid addition salt thereof.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the compound of formula (I) is
or a pharmacologically acceptable acid addition salt thereof.

### Claim 5 (depends on 1)

The method according to claim 1, wherein the compound of formula (I) is
or a pharmacologically acceptable acid addition salt thereof.

### Claim 6 (depends on 1)

The method according to claim 1, wherein the compound of formula (I) is
or a pharmacologically acceptable acid addition salt thereof.

### Claim 7 (depends on 1)

The method according to claim 1, wherein the compound of formula (I) is
or a pharmacologically acceptable acid addition salt thereof.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the compound of formula (I) is
or a pharmacologically acceptable acid addition salt thereof.

### Claim 9 (depends on 1)

The method according to claim 1, wherein the compound of formula (I) is
or a pharmacologically acceptable acid addition salt thereof.