# US 7,410,972 B2 · Compounds

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- Number: US 7,410,972 B2
- Document ID: US7410972B2
- Status: Granted
- Kind: B2
- Application number: 10/499,102
- Filed: 2002-12-17
- Published: 2005-04-07
- Granted: 2008-08-12
- Earliest claimed: 2001-12-18
- Assignees: AstraZeneca AB
- Inventors: Andrew Baxter; Timothy Johnson; Nicholas Kindon; Bryan Roberts; John Steele; Michael Stocks; Nicholas Tomkinson
- Web page: https://patentgrep.com/patent/US7410972B2

## CPC

- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- A61P 11/06: Antiasthmatics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 233/56: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D 249/08: 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 409/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention provides N-pyrazinyl-thienylsulphonamides of formula (I) for use in the treatment of chemokine mediated diseases. Particularly inflammatory diseases, such as asthma

## Claims

### Claim 1

A compound of formula (I) or a pharmaceutically acceptable salt thereof:
in which:
R1, R2 and R3 are independently hydrogen, halogen, cyano, CF3, or C1-6 alkyl;
R4is
halogen, CO2R12,
C1-6 alkoxy where the alkyl group may form a 3-6 membered saturated ring or may be substituted with 1-3 fluorine atoms or a cyano group;
C3-6 alkenyloxy or C3-6 alkynyloxy where either may be optionally substituted with hydroxy or NR14R15;
OC1-6 alkyl-X—C1-6 alkyl where the alkyl groups may form a 3-6 membered saturated ring;
OC1-6 alkylR11, or OC2-6 alkyl-X—R11 where the alkyl group may form a 3-6 membered saturated ring and is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR14R15, SR13, S(O)2R13, S(O)13;
OC1-6 alkylR16;
R5 and R6 are independently
hydrogen, cyano, halogen, CO2R12, CONR14R15;
C1-6 alkyl optionally substituted by hydroxy, NR14R15, or 1-3 fluorines;
C1-6 alkylR11 or XCH(R11)C1-6 alkyl or XCH(R16)C1-6 alkyl where the alkyl group may be optionally substituted with 1-3 groups selected from hydroxy, and NR14R15;
NR14R15; N(R11)R11; X—(CH2)qNR14R15; (CH2)nNR14R15;
C3-6 alkynyl or C3-6 alkenyl optionally branched and optionally substituted with 1-3 groups selected from hydroxy, cyano, halogen and ═O;
R11; X—R11; X—R12; X—C1-6alkylR16;X—R16; X—(CH2)nCO2R12; X—(CH2)nCONR14R15;
X—(CH2)nR11; X—(CH2)nCN; X—(CH2)qOR12; (CH2)nOR12;
(CH2)n-X—R11; X—(CH2)qNHC(O)NHR12; X—(CH2)qNHC(O)R12;
X—(CH2)qNHS(O)2R12; X—(CH2)qNHS(O)2R11; X—C3-6 alkenyl; X—C3-6 alkynyl;
n is 1 ,2, 3, 4 or 5;
q is 2, 3, 4, 5 or 6;
X is NR13, O, S, S(O), S(O)2;
R11 is
an aryl group or a 5-7 membered heteraromatic ring containing 1-4 heteroatoms selected from nitrogen, oxygen or sulphur each of which can be optionally substituted by 1-3 groups selected from halogen, C(O)NR14R15, C(O)OR12, hydroxy, ═O,═S, CN, NO2,
NR14R15, X(CH2)qNR14R15, (CH2)nNR14R15, (CH2)nOH, SR13, S(O)R13, S(O)2R13 C1-6 alkyl-X—C1-6 alkyl, C1-6 alkyl or C1-6 alkoxy where the alkyl group may form a 3-6 membered ring or is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR14R15, SR13, S(O)R13, S(O)2R13;
R12 and R13 are independently hydrogen or C1-6 alkyl where the alkyl group may be substituted with 1-3 fluorine atoms or may form a saturated 3-6 membered ring;
R14 and R15 are independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)qOH, or R14 and R15 together with the nitrogen atom to which they are attached form a 4-8 membered saturated ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulphur and optionally substituted by C1-6 alkyl, C1-6 alkyl-OH, or hydroxy; and
R16 is a 4-8 membered saturated ring containing 1-3 heteroatoms selected from nitrogen, oxygen or sulphur and optionally substituted with 1-3 groups selected from hydroxy, cyano, halogen and ═O.

### Claim 2 (depends on 1)

The compound according to claim 1 in which the thienyl moiety is linked to the sulphonamide at the 2-position of the ring.

### Claim 3 (depends on 1)

The compound according to claim 1 in which R1, R2 and R3 are all hydrogen or two are hydrogen and the other is chloro, bromo or methyl.

### Claim 4 (depends on 1)

The compound according to claim 1 in which R4 is C1-6, alkoxy, phenoxy, 2-furanylmethoxy, bromo, 2-methoxyethoxy, (5-methyl-3-isoxazolyl)methoxy, 2-pyridylmethoxy, 3-pyridazinylmethoxy, 2-(1-imidazolyl)ethoxy or 4-methoxyphenylmethoxy.

### Claim 5 (depends on 1)

The compound according to claim 1 in which R5 is hydrogen, halogen, phenyl, C1-6 alkyl, cyano or 2-ammothanethiol.

### Claim 6 (depends on 1)

The compound according to claim 1 in which R6 is hydrogen, C1-6 alkyl or halogen.

### Claim 7 (depends on 1)

The compound according to claim 1 which is:
N-(5-Bromo-3-methoxy-2-pyrazinyl)-5-chloro-2-thiophenesulphonamide
N-(5-Bromo-3-ethoxy-2-pyrazinyl)-5-chloro-2-thiophenesulphonamide
N-(5-Bromo-3-methoxy-2-pyrazinyl)-4,5-dichloro-2-thiophenesulphonamide
5-Chloro-N-(3-methoxy-5-phenyl-2-pyrazinyl)-2-thiophenesulphonamide
N-(5-Bromo-3-phenoxy-2-pyrazinyl)-5-chloro-2-thiophenesulphonamide
N-(5-Bromo-3-methoxy-2-pyrazinyl)-2-thiophenesulphonamide N-[5-Bromo-3-(2-furanylmethoxy)-2-pyrazinyl]-5-chloro-2-thiophenesulphonamide
5-Chloro-N-(3 ,5-dibromo-2-pyrazinyl)-2-thiophenesulphonamide
5-Chloro-N-(3-methoxy-5-methyl-2-pyrazinyl)-2-thiophenesulphonamide
5-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-2-thiophenesulphonamide
5-Bromo-N-(5-bromo-3-methoxy-2-pyrazinyl)-2-thiophenesulphonamide
5-Chloro-N-(6-chloro-3-methoxy-2-pyrazinyl)-2-thiophenesulphonamide
3-Bromo-N-(5-bromo-3-methoxy-2-pyrazinyl)-5-chloro-2-thiophenesulphonamide
N-(5-Bromo-3-methoxy-2-pyrazinyl)-3-thiophenesulphonamide
5-Chloro-N-(5 ,6-dichloro-3-methoxy-2-pyrazinyl)-2-thiophenesulphonamide
5-Chloro-N-[5-bromo-3-(2-methoxyethoxy)-2-pyrazinyl]-2-thiophenesulphonamide
5-Chloro-N-[5-bromo-3-[2-(1-imidazolyl)ethoxy]-2-pyrazinyl]-2-thiophenesulphonamide
5-Bromo-N-(6-chloro-3-methoxy-2-pyrazinyl)-2-thiophenesulphonamide
5-Bromo-N-(5-chloro-3-methoxy-2-pyrazinyl)-2-thiophenesulphonamide
5-Chloro-N-[6-chloro-3-(2-furanylmethoxy)-2-pyrazinyl]-2-thiophenesulphonamide
5-Chloro-N-[6-chloro-3-(5-methyl-3 -isoxazolylmethoxy)-2-pyrazinyl]-2-thiophenesulphonamide
5-Chloro-N-[6-chloro-3-(2-pyridinylmethoxy)-2-pyrazinyl]-2-thiophenesulphonamide
5-Chloro-N-[5-methyl-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2-thiophenesulphonamide
5-Chloro-N-[5-methyl-3-(3-pyridazinylmethoxy)-2-pyrazinyl]-2-thiophenesulphonamide
5-Chloro-N-[3-(2-pyridinylmethoxy)-2-pyrazinyl]-2-thiophenesulphonamide
5-Chloro-N-(3-methoxy-2-pyrazinyl)-2-thiophenesulphonamide
5-Chloro-N-(5,6-dimethyl-3 -methoxy-2-pyrazinyl)-2-thiophenesulphonamide
N- [5-Chloro-3-methoxy-2-pyrazinyl]-5-methyl-2-thiophenesulphonamide
5-Methyl-N-[5-methyl-3-methoxy-2-pyrazinyl]-2-thiophenesulphonamide
N-[5-{(2-Aminoethyl)sulpanyl}-3-methoxypyrazin-2-yl]-5-chloro-2-thiophenesulphonamide
5-Chloro-N-[5-cyano-3-methoxypyrazin-2-yl]-2-thiophenesulphonamide
N-[5-Bromo-3-(4-methoxybenzyloxy)pyrazin-2-yl]-5-chloro -2-thiophenesulphonamide or a pharmaceutically acceptable salt thereof.

### Claim 8

A compound of formula (IA)
in which:
R1, R2 and R3 are independently hydrogen, C1-6 alkyl or halogen;
R4 is halogen, C1-6 alkoxy or OR9;
R5 and R6 are independently hydrogen, halogen, C1-6 alkoxy, C1-6 alkylthio, cyano,R9, OR9, NR9R10, SR9, S(CH2)nCO2H, S(CH2)nCO2R12, S(CH2)nCONR12R13, S(CH2)nR11 or a 5- to 7-membered heteroaromatic or saturated ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulphur;
n is 1,2 or 3;
R9 and R10 are independently hydrogen, C1-6 alkyl optionally substituted by hydroxy, C1-6 alkoxy or NHCOC1-6 alkyl, or R9 and R10 optionally substituted aryl, C1-6 alkyl-aryl or C1-6 alkyl-R11 or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 8-membered saturated ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulphur and optionally substituted by C1-6 alkyl or C1-6 alkyl-OH; and
R11 is a 5- to 7-membered heteraromatic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulphur and optionally substituted by C1-6 alkyl; and
R12 and R13 are independently hydrogen or C1-6 alkyl.

### Claim 9 (depends on 8)

The compound according to claim 8 in which R1, R2 and R3 are all hydrogen or two are hydrogen and the other is chloro or methyl.

### Claim 10 (depends on 8)

The compound according to claim 8 in which R4 is C1-6 alkoxy, phenoxy, 2-furanylmethoxy, bromo, 2-methoxyethoxy, (5-methyl -3-isoxazolyl)methoxy, 2-pyridylmethoxy, 3-pyridazinylmethoxy, methoxy or 2-(1-imidazolyl)ethoxy.

### Claim 11 (depends on 8)

The compound according to claim 8 in which R5 is halogen, phenyl or C1-6 alkyl.

### Claim 12 (depends on 8)

The compound according to claim 8 in which R6 is hydrogen, C1-6 alkyl and halogen.

### Claim 13 (depends on 1)

A process for the preparation of a compound of formula (I) as claimed in claim 1 which comprises reaction of a compound of formula (II):
where R4, R5 and R6 are as defined in formula (I) or are protected derivatives thereof with a compound of formula (III):
where R1, R2 and R3 are as defined in formula (I) or are protected derivatives thereof and LG is a leaving group, and optionally thereafter
removing any protecting groups,
forming a pharmaceutically acceptable salt.

### Claim 14 (depends on 1)

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

### Claim 15 (depends on 1, 14)

A process for the preparation of a pharmaceutical composition as claimed in claim 14 which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 with a pharmaceutically acceptable adjuvant, diluent or carrier.

### Claim 16 (depends on 1)

A method of treating asthma in a patient in need thereof, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1.