# US 7,408,065 B2 · P2X7 receptor antagonists and their use

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- Number: US 7,408,065 B2
- Document ID: US7408065B2
- Status: Granted
- Kind: B2
- Application number: 10/558,898
- Filed: 2004-06-01
- Published: 2006-12-28
- Granted: 2008-08-05
- Earliest claimed: 2003-06-02
- Assignees: AstraZeneca AB
- Inventors: Richard Evans; Christine Eyssade; Rhonan Ford; Barrie Martin; Toby Thompson; Paul Willis
- Web page: https://patentgrep.com/patent/US7408065B2

## CPC

- A61K 31/47: Quinolines; Isoquinolines
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/10: for osteoporosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 215/38: Nitrogen atoms (nitro radicals C07D215/18)
- C07D 215/48: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 217/22: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 487/08: Bridged systems
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The invention provides compounds of formula (IA), processes for their preparation, pharmaceutical compositions containing them, and their use in therapy.

## Claims

### Claim 1

A compound of formula (III)
or a pharmaceutically acceptable salt thereof,
wherein
R1 is selected from halogen or C1-6 alkyl,
X is C(O)NH or NHC(O);
n is 1;
each R5 and each R6 are independently selected from hydrogen or C1-3alkyl, or R5 and R6 together with the carbon atom to which they are both attached forms a C3-6cycloalkcyl ring,
R2 is an optionally substituted cycloalkyl group containing 5 to 7 carbon atoms; and
R3 is hydrogen, or a group R7, OR7, SR7, NR7R8, where R7 and R8 are independently selected from hydrogen, optionally substituted C1-10alkyl, an optionally substituted cycloalkyl or an optionally substituted heterocyclic group, or R7 and R8 together with the nitrogen to which they are attached form an optionally substituted heterocyclic ring which may contain additional heteroatoms, and may further comprise bridging groups.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R3 is a group of formula (IIB)
where X1 represents a group >N—R11 and R11 is hydrogen or a C1-5alkyl group which may be optionally substituted by one or more substituents selected from hydroxy, halogen or C1-6alkoxy;
s is 0 or 1;
R9 represents a bond or a C1-C5 alkylene group, which may be optionally substituted,
R10 represents hydrogen, hydroxyl, carboxy, a group —NR19R20, an optionally substituted carbocyclic or an optionally substituted heterocyclic ring, either or which may include bridging groups,
where R19 and R20 are independently selected from hydrogen, pyrrolidine, piperazine, piperidine, C1-6alkylcarbonyl, C2-7alkenyl, optionally substituted C1-7alkyl, or C(O)NHS(O2)R21 where R21 is C1-5alkyl, provided that when s is 1 and R9 is a bond, R10 is other than hydroxy, carboxy or a group —NR19R20.

### Claim 3 (depends on 2)

A compound according to claim 2, wherein in formula (IIB) R9 represents a C1-5 alkylene group which can be optionally substituted; and R10 represents hydrogen, hydroxyl, carboxyl, or a group —NR19R20.

### Claim 4 (depends on 2)

A compound according to claim 2, wherein R10 represents a 4- to 9-menabered carbocydic or heterocyctie ring, either of which is optionally substituted by at least one substituent.

### Claim 5 (depends on 2)

The compound of claim 2, wherein s is 0, R9 is a bond and R10 is a group NR33 and R34 where R33 and R34 together with the nitrogen atom to which they are attached form a saturated five or six-membered heterocyclic ring optionally substituted by one or two substituents independently selected from, amino, hydroxy, hydroxyC1-3alkylamino, C1-C2 alkyl and C1-C2 hydroxyalkyl.

### Claim 6 (depends on 1)

A compound of formula (III) according to claim 1, or pharmaceutically acceptable salt thereof, selected from the group consisting of:
N-[6-Chloro-2-(4-piperidinylmethyl)-5-quinolinyl]-cyclohexaneacetamide, dihydrochloride,
N-[6-Chloro-2-(1-piperazinyl)-5-quinolinyl]-cyclohexaneacetamide, dihydrochloride,
N-[6-Chloro-2-[methyl[3-methylamino)propyl]amino]-5-quinolinyl]-cyclohexaneacetamide, dihydrochloride,
6-Chloro-N-(cyclohexylmethyl)-2-methyl-5-quinolinecarboxamide, hydrochloride,
N-[6-Chloro-2-[(3-hydroxypropyl)amino]-5-quinolinyl]-cyclohexaneacetamide, hydrochloride,
N-[6-Chloro-2[[(2R)-2,3-dihydroxypropyl]amino]-5-quinolinyl]-cyclohexaneacetamide,
4-[[6-Chloro-5-[(cyclohexylacetyl)amino]-2-quinolinyl]amino]-butanoic acid,
N-[6-Chloro-2-[methyl[3-(methylamino)propyl]amino]-5-quinolinyl]-4-(trifluoromethyl)-cyclohexaneacetamide, dihydrochloride,
N-[6-Chloro-2-(1-piperazinyl)-5-quinolinyl]-4-(trifluoromethyl)-cyclohexaneacetamide,
N-[6-Chloro-2-(hexahydro-1H-1,4-diazepin-1-yl)-5-quinolinyl]-cyclohexaneacetamide,
N-[6-Chloro-2-[(cis-3,5-dimethyl-1-piperazinyl]-5-quinolinyl]-cyclohexaneacetamide,
N-[6-Chloro-2-(4-methyl-1-piperazinyl)-5-quinolinyl]-cyclohexaneacetamide, dihydrochloride,
N-[6-Chloro-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-5-quinolinyl]-cyclohexaneacetamide, acetate,
N-[6-Chloro-2-[(3R)-3-pyrrolidinylamino]-5-quinolinyl]-cyclohexaneacetamide, dihydrochloride,
N-[2-[3-(Ethylamino)propyl]-6-methyl-5-quinolinyl]-cyclohexaneacetamide, dihydrochloride,
N-[6-Chloro-2-[3-(ethylamino)propyl]-5-quinolinyl]-cyclohexaneacetamide, dihydrochloride,
N-[6-Chloro-2-[[2-[(hydroxyethyl)amino]ethyl]amino]-5-quinolinyl]-cyclohexaneacetamide, dihydrochloride,
N-[6-Chloro-2-[3-[(3-hydroxypropyl)amino]propyl]-5-quinolinyl]-cyclohexaneacetamide,
N-[2-(3-Aminopropyl)-6-chloro-5-quinolinyl]-cyclohexaneacetamide,
N-[6-Chloro-2-[3-[[[(methylsulfonyl)amino]carbonyl]amino]propyl]-5-quinolinyl]-cyclohexaneacetamide,
N-[2-[3-(Butylamino)propyl]-6-chloro-5-quinolinyl]-cyclohexaneacetamide dihydrochloride,
N-[6-Chloro-2-[methyl[3-(methylamino)propyl]amino]-5-quinolinyl]-1-cyclohexyl-cyclopropanecarboxamide, hydrochloride,
N-[6-Chloro-2-(1-piperazinyl)-5-quinolinyl]-1-cyclohexyl-cyclopropanecarboxamide,
N-[6-Chloro-2-[(3R)-3-hydroxy-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide,
N-[6-Chloro-2-[(3S)-3-hydroxy-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide,
N-[2-[(3R)-3-amino-1-pyrrolidinyl]-6-chloro-5-quinolinyl]-cyclohexaneacetamide,
N-[2-[(3S)-3-amino-1-pyrrolidinyl]-6-chloro-5-quinolinyl]-cyclohexaneacetamide,
N-[2-(4-amino-1-piperidinyl)-6-chloro-5-quinolinyl]-cyclohexaneacetamide,
N-[6-Chloro-2-[(3R)-3-(methylamino)-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide,
N-[6-Chloro-2-[(3R)-3-[(2-hydroxyethyl)amino]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide,
N-[6-Chloro-2-[(3S)-3-(methylamino)-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide,
N-[6-Chloro-2-[(3S)-3-[(2-hydroxyethyl)amino]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide,
N-[6-Chloro-2-[(3R)-3-hydroxy-1-piperidinyl]-5-quinolinyl]-cyclohexaneacetamide,
N-[2-[(3S)-3-amino-1-pyrrolidinyl]-6-methyl-5-quinolinyl]-cyclohexaneacetamide,
N-[6-Methyl-2-(1-piperazinyl)-5-quinolinyl]-cyclohexaneacetamide,
N-[6-Chloro-5-[(cyclohexylacetyl)amino]-2-quinolinyl]-glycine,
N-[6-Chloro-5-[(cyclohexylacetyl)amino]-2-quinolinyl]-β-alamine,
6-Chloro-N-(cyclohexylmethyl)quinoline-5-carboxamide, and
6-Chloro-N-(cyclohexylmethyl)-2-(1-piperazinyl)-5-quinolinecarboxamide, dihydrochloride.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising a compound of formula (III), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

### Claim 8 (depends on 1, 7)

A process for the preparation of a pharmaceutical composition as claimed in claim 7 which comprises mixing a compound of formula (III), or a pharmaceutically acceptable salt thereof, as defined in claim 1 with a pharmaceutically acceptable adjuvant, diluent or carrier.