Thieno[2,3-d]pyrimidine-2,4-diones

• US 6,300,334 B1
• Filed: 10/13/1999
• Issued: 10/09/2001
• Est. Priority Date: 08/28/1998
• Status: Expired due to Fees

• Current Assignee: Astrazeneca UK Limited (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Cooper, Martin, Thorne, Philip, Perry, Matthew, Bantick, John
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): MCKENZIE, THOMAS C
• Application Number:
  US09/402,837
• Time in Patent Office: 727 Days
• Field of Search: 514/258, 514/278
• US Class Current: 514/260.1
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/08 for leprosy
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems

Abstract

Compounds of formula (I):

wherein R¹, R², and R³ are defined in the specification. The compounds are useful for treating or reducing the risk of reversible obstructive airways disease.

Claims

1. A compound of formula (I):

wherein;

R represents a group —

C(O)Ar¹ or —

C(R⁴)(R⁵)Ar¹;

Art represents a heterocyclic group comprising a total of from 5 to 10 atoms which include from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, which group Ar¹ may be optionally substituted by one or more substituents independently selected from oxo, hydroxyl, C_1-4alkyl, C_1-4alkoxy, halogen, trifluoromethyl, amino, nitro, cyano, trifluoromethoxy, phenoxy, —

CH₂N(R⁶)₂, —

NHSO₂CF₃, C_1-4alkylsulfonylamino, —

NHC(O)R^6a, CO₂R⁷ or —

C(O)NR⁸R^8a, with the proviso that Ar¹ does not represent an optionally substituted benzofuranyl, benzothienyl, indolyl, quinolyl or isoquinolyl group;

R⁴ represents a hydrogen atom or a C_1-4 alkyl group;

R⁵ represents a hydrogen atom or a hydroxyl group;

each R⁶ independently represents a hydrogen atom or a C_1-4 alkyl group;

R^6a represents a hydrogen atom or C_1-6 alkyl, phenyl, pyridinyl, (phenyl) C_1-4 alkyl or (pyridinyl) C_1-4 akyl, each of which may be optionally substituted by one or more substituents independently selected from C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylcarbonylamino, halogen or trifluoromethyl;

R⁷ represents a hydrogen atom or a C_1-4 alkyl group;

R⁸ and R^8a each independently represent a hydrogen atom or a C_1-4 alkyl, phenyl or pyridinyl group;

R¹ and R² each independently represent a hydrogen atom or a C_1-6 alkyl, C_3-6 alkenyl, CH₂C_3-5 cycloalkyl or C_3-6 cycloalkyl group;

R³ a hydrogen atom or a group X—

R⁹ or X—

Ar²;

X represents an oxygen atom, S(O)_n, C(O)NR¹⁰, C(O)O, NH(CO)NR¹⁰, NH(CO)O or SO₂NR¹⁰, with the proviso that when X represents an oxygen atom and R represents a group —

C(R⁴)(R⁵)Ar¹, then R⁴ and R⁵ both represent a hydrogen atom;

n is 0, 1 or 2;

R⁹ represents a methyl group optionally substituted by one or more substituents independently selected from cyano, carboxyl, C_1-5 alkoxycarbonyl, 5-tetrazolyl or C(O)NR¹¹R¹², or R⁹ represents a C_2-6 alkyl or C_3-6 alkenyl group, each of which may be optionally substituted by one or more substituents independently selected from hydroxyl, cyano, carboxyl, C_1-5 alkoxy, C_1-5 alkoxycarbonyl, 5-tetrazolyl, azido, phthalimido, SO₂NH₂, C(O)NR¹¹R¹², NR¹³R¹⁴, NHC(O)R¹⁵ or NHSO₂R¹⁶ where R¹¹, R¹², R¹³ and R¹⁴ each independently represent a hydrogen atom or a C_1-4 alkyl group, R¹⁵ represents a C_1-4 alkyl, C_1-4 alkoxy, amino or (di)C_1-4alkylamino group or an alkoxyalkylene group containing up to 6 carbon atoms, and R¹⁶ represents a C_1-4 alkyl or trifluoromethyl group;

or, additionally, in the case where X represents C(O)NR¹⁰, NH(CO)NR¹⁰ or SO—

NR¹⁰, R⁹ and R¹⁰ together with the nitrogen atom to which they are attached may form a 4- to 7-membered saturated heterocyclic ring which may be optionally substituted by one or more hydroxyl groups;

R¹⁰ represents a hydrogen atom or a C_1-6alkyl group or is linked to as defined above; and

Ar² is phenyl, pyridinyl, thienyl, pyridone or pyridine N-oxide, each of which may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, nitro, amino, NHSO₂CF₃, C_1-4 alkyl, C_1-4 alkoxy, bis-C_1-4alkanesulfonylamino, C_1-4alkylcarbonylamino or C_1-4alkoxycarbonylamino;

or a pharmaceutically-acceptable salt or solvate thereof.

2. A compound according to claim 1, wherein R represents a group —

C(R⁴)(R⁵)Ar¹.

3. A compound according to claim 2, wherein R⁴ represents a hydrogen atom.

4. A compound according to claim 1, wherein Ar¹ represents a benzimidazolyl, pyridinyl, thienyl, thiazolyl, pyrazolyl, benzotriazolyl, indazolyl, pyridopyrrolyl or benzothiazolyl group optionally substituted as defined in claim 1.

5. A compound according to claim 1, wherein R¹ and R² each independently represent a C_1-6 alkyl group.

6. A compound according to claim 1, wherein R³ represents a hydrogen atom.

7. A compound according to claim 1 relected from:

(±

)-6-[1-Hydroxy-1-(1-methyl-1H-benzimidazol-2-yl)methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

3-Methyl-6-[(1-methyl-1H-benzimidazol-2-yl)methyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

(±

)-6-[1-Hydroxy-1-(2-pyridinyl)methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

(±

)-6-[1-Hydroxy-1-(3-pyridinyl)methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

(±

)-6-[1-Hydroxy-1-(4-pyridinyl)methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

(±

)-6-[1-Hydroxy-1-(2-thienyl)methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

(±

)-6-[1-(5-Chloro-2-thienyl)-1-hydroxymethyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

(±

)-6-[1-Hydroxy-1-(3-thienyl)methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

(±

)-6-[1-Hydroxy-1-(2-thiazolyl)methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

(±

)-6-[1-(4-Chloro-1-methyl-1H-pyrazol-3-yl)-1-hydroxymethyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

3-Methyl-1-(2-methylpropyl)-6-(2-pyridinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

3-Methyl-1-(2-methylpropyl)-6-(3-pyridinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

3-Methyl-1-(2-methylpropyl)-6-(4-pyridinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

3-Methyl-1-(2-methylpropyl)-6-(2-thienylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)dione,

6-(5-Chloro-2-thienylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

3-Methyl-1-(2-methylpropyl)-6-(2-thiazolylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-[(4-Chloro-1-methyl-1H-pyrazol-3-yl)methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-[(1H-Benzimidazol-1-yl)methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-(2H-Benzotriazol-2-ylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-(1H-Benzotriazol-1-ylmethyl)-3-methyl-1-(2-methylpropyl) thieno[2,3-d]-pyrimidine-2,4(1H,3H)-dione,

6-(2H-Indazol-2-ylmethyl)-3-methyl-1-(2-methylpropyl) thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-(1H-Indazol-1-ylmethyl)-3-methyl-1-(2-methylpropyl) thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

3-Methyl-1-(2-methylpropyl)-6-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4-1H,3H)-dione,

(±

)-6-[1-Hydroxy-1-(benzothiazol-2-yl)methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-(Benzothiazol-2-yl)methyl-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-[1-Hydroxy-1-(1-methyl-1H-benzimidazol-2-yl)methyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione,

3-Methyl-6-[(1-methyl-1H-benzimidazol-2-yl)methyl]-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione,

(3R)-1-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(3-pyridinyl)methyl-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]sulfonyl}pyrrolidin-3-ol,

1-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(3-pyridinyl)methyl-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]sulfonyl}pyrrolidine,

±

-6-[(1H-Benzimidazol-2-yl)-1-hydroxymethyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-[(1H-Benzimidazol-1-yl)methyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-([1H-Benzimidazol-1-yl]methyl)-1-(cyclopropylmethyl)-3-methyl-thieno[2,3-9]pyrimidine-2,4(1H, 3H)-dione,

1-(Cyclopropylmethyl)-6-[1-hydroxy-1-(1-methyl-1H-benzimidazol-2-yl)methyl]-3-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione,

1-(Cyclopropylmethyl)-6-[(1-methyl-1H-benzimidazol-2-yl)methyl]-3-miethylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione,

1-({6-[(1H-Benzimidazol-1-yl)methyl]-1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl}carbonyl)pyrrolidine,

1-({1,2,3,4-Tetrahydro-6-[(1-methyl-1H-benzimidazol-2-yl)methyl]-1-(cyclopropylmethyl)-3-methyl-2,4-dioxothieno[2,3-d]pyrimidin-5-yl}carbonyl)azetidine,

5-[(3-Hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-[(pyridin-3-yl)carbonyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

5-[(3-Hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-[1-hydroxy-1-(pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

5-[(3-Hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-[1-(pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

3-Methyl-1-(2-methylpropyl)-6-[(pyridin-3-yl)carbonyl]-5-[(2-thienyl)thio]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

3-Methyl-1-(2-methylpropyl)-6-[1-(pyridin-3-yl)methyl]-5-[(2-thienyl)thio]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

5-(3-Hydroxypropoxy)-3-methyl-1-(2-methylpropyl)-6-[1-(pyridin-3-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

3-Methyl-6-[(1-methyl-1H-benzimidazol-2-yl)carbonyl]-5-[(1-methylethyl)thio]-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-[Hydroxy(1-methyl-1H-benzimidazol-2-yl)methyl]-3-methyl-5-[(1-methylethyl)thio]-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

3-Methyl-6-[(1-methyl-1H-benzimidazol-2-yl)methyl]-5-[(1-methylethyl)thio]-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

3-Methyl-6-[(1-methyl-1H-benzimidazol-2-yl)methyl]-5-[(1-methylethyl)sulfonyl]-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

3-Methyl-5-[(1-methylethyl)thio]-1-(2-methylpropyl-6-(3-pyridinylcarbonyl)-thieno[2,3-d]pyrimidine 2,4(1H,3H)-dione,

6-(Hydroxy-3-pyridinylmethyl)-3-methyl-5-[(1-methylethyl)thio]-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

3-Methyl-5-[(1-methylethyl)thio]-1-(2-methylpropyl)-6-(3-pyridinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-(1H-Benzimidazol-1-ylmethyl)-3-methyl-1-(2-methylpropyl)-5-(2-thienylthio)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-[(2-Chloro-1H-benzimidazol-1-yl)methyl-3-methyl-1-(2-methylpropyl)-5-(2-thienylthio)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-[(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl]-3-methyl-1-(2-methylpropyl)-5-(2-thienylthio)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-[Hydroxy[6-(trifluoromethyl)-2-pyridinyl]methyl]-3-methyl-1-(2-methylpropyl)-5-(2-thienylthio)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

6-(1H-Benzimidazol-1-ylmethyl)-3-methyl-5-[(1-methylethyl)thio]-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,

3-Methyl-5-[(1-methylethyl)thio]-1-(2-methylpropyl)-6-[[3-oxo-1,2-benzisothiazol-2(3H)-yl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, S,S-dioxide,

2,3-Dihydro-2-[[1,2,3,4-tetrahydro-3-methyl-5-[(1-methylethyl)thio]-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]methyl]-1,4-phthalazinedione and their pharmaceutically acceptable salts and solvates.

8. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, according to claim 1 in association with a pharmaceutically-acceptable adjuvant, diluent or carrier.

9. A process for the preparation of a compound of formula (I) as defined in claim 1 which comprises:

(a) when R³ represents a hydrogen atom or a group X—

R⁹ or X—

Ar² where X represents C(O)NR¹⁰, C(O)O, NH(CO)NR¹⁰ or NH(CO)O and R represents —

C(R⁴)(R⁵)Ar¹ where R⁴ is a hydrogen atom or a C_1-4 alkyl group, R⁵ is a hydroxyl group and Ar¹ is attached through a carbon atom to —

C(R⁴)(R⁵), reacting a compound of general formula

 

wherein R^3′

represents a hydrogen atom or a group X—

R⁹ or X—

Ar² in which X represents C(O)NR¹⁰, C(O)O, NH(CO)NR¹⁰ or NH(CO)O, and R¹, R², R⁹, R¹⁰ and Ar² are as defined in formula (I), with a compound of general formula (III), Ar¹—

C(O)R⁴, wherein R⁴ and Ar¹ are as defined in formula (I) and Ar¹ is attached through a carbon atom to —

C(O)R⁴;

or

(b) when R represents —

C(R⁴)(R⁵)Ar¹ where R⁴ is a hydrogen atom, R⁵ is a hydroxyl group and Ar¹ is attached through a carbon atom to —

C(R⁴)(R⁵), reacting a compound of general formula

 

wherein R¹, R² and R³ are as defined in formula (I), with a compound of general formula (V), Ar¹—

M, wherein M represents a metal ion (e.g. lithium) and Ar¹ is as defined in formula (I);

or

(c) when X represents S(O)n and R represents —

C(R⁴)(R⁵)Ar¹ where R⁴ is a C_1-4 alkyl group, R⁵ is a hydroxyl group and Ar¹ is attached through a carbon atom to —

C(R⁴)(R⁵), reacting a compound of general formula

 

wherein R^3″

represents S—

R⁹ or S—

Ar² and R¹, R², R⁹, Ar¹ and Ar² are as defined in formula (I), with a compound of general formula (VII), R^4′

-MgHal, wherein R^4′

represents a C_1-4 alkyl group and Hal represents a halogen atom, optionally followed by an oxidation reaction;

or

(d) when X represents SO₂NR¹⁰, reacting a corresponding compound of formula (I) in which R³ represents a hydrogen atom, with sulphur dioxide in the presence of a base, followed by an oxidation step and then reaction with a compound of general formula (VIII), HNR¹⁰R¹⁷, where R¹⁷ represents a group R⁹ or Ar² and R⁹, R¹⁰ and Ar² are as defined in formula (I);

or

(e) when R represents —

C(R⁴)(R⁵)Ar¹ where R⁵ represents a hydrogen atom, reacting a corresponding compound of formula (I) in which R⁵ represents a hydroxyl group, with a reducing agent;

or

(f) when R represents —

C(R⁴)(R⁵)Ar¹ where R⁴ is a hydrogen atom or a C_1-4 alkyl group, R⁵ is a hydrogen atom and Ar¹ is attached through a nitrogen heteroatom to —

C(R⁴)(R⁵), reacting a compound of general formula

 

wherein Hal represents a halogen atom and R¹, R², R³ and R⁴ are as defined in formula (I), with a compound of general formula (X), Ar¹—

H, wherein Ar¹ is as defined in formula (I), in the presence of a base;

or

(g) when R reperesents a group —

C(O)Ar¹, oxidising a corresponding compound of formula (I) in which R⁴ is a hydrogen atom and R⁵ is a hydroxyl group;

or

(h) when R³ reperesent a hydrogen atom or a group X—

R or X—

Ar² where X represents C(O)HR¹⁰, C(O)O, NH(CO)NR¹⁰ or NH(CO)O and R represents a group —

C(O)Ar¹, reacting a compound of formula (II) as defined above, with a compound of general formula (XI), AR¹CON(CH₃)OCH₃ wherein Ar¹ is as defined in formula (I), in the presence of a base;

or

(j) when X represents an oxygen atom and R represents a group —

C(O)Ar¹, reacting a compound of general formula

 

wherein R¹, R² and Ar¹ are as defined in formula (I), with a compound of general formula (XIII), R¹⁷—

L, wherein L represents a leaving group and R¹⁷ is as defined in (d) above;

or

(k) when X represents an oxygen atom and R represents a group —

CH₂Ar¹, reacting a compound of general formula

 

with a compound of formula (XIII) as defined in (j) above;

and optionally after (a), (b), (c), (d), (e), (f), (g), (h), (j) or (k) converting the compound of formula (I) to a further compound of formula (I) and, if desired, forming a pharmaceutically acceptable salt or solvate thereof.

10. A process for the preparation of a pharmaceutical composition as claimed in claim 8 which comprises mixing a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, according to claim 1 with a pharmaceutically-acceptable adjuvant, diluent or carrier.

11. A method of treating allograft rejection which comprises administering to a patient a therapeutically effective amount of a compound (I) or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1.

12. A method of treating, or reducing the risk of, a reversible obstructive airways disease in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as claimed in claim 1.