Benzenesulfonamide-derivatives and their use as medicaments

• US 6,667,342 B1
• Filed: 08/22/2000
• Issued: 12/23/2003
• Est. Priority Date: 03/17/1998
• Status: Expired due to Fees

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Whittamore, Paul Ro, Clarke, David S, Nowak, Thorsten, Burrows, Jeremy N, Butlin, Roger J
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): Balasubramanian, Venkataraman
• Application Number:
  US09/622,678
• Time in Patent Office: 1,218 Days
• Field of Search: 564/85, 564/86, 564/89, 544/56, 544/159, 544/213, 544/297, 544/326, 544/358, 544/407, 546/244, 546/247, 546/248, 548/342.1, 548/570, 514/603, 514/604, 514/227.5, 514/231.2, 514/256, 514/241, 514/247, 514/269, 514/252.1, 514/315, 514/347, 514/396, 514/401
• US Class Current: 514/603
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• 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: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/04 with a four-membered ring
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 311/46 Y being a hydrogen or a carbon atom
• CPC Class Codes: C07C 311/51 Y being a hydrogen or a carbon atom
• CPC Class Codes: C07C 311/60 having nitrogen atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 317/34 having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
• CPC Class Codes: C07C 323/49 to sulfur atoms
• CPC Class Codes: C07C 323/62 having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
• CPC Class Codes: C07D 207/48 Sulfur atoms
• CPC Class Codes: C07D 209/08 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 211/46 having a hydrogen atom as the second substituent in position 4
• CPC Class Codes: C07D 211/56 Nitrogen atoms nitro radicals C07D211/38
• CPC Class Codes: C07D 211/96 Sulfur atom
• CPC Class Codes: C07D 213/42 : having hetero atoms attached to the substituent nitrogen atom nitro radicals C07D213/26
• CPC Class Codes: C07D 213/76 : to which a second hetero atom is attached nitro radicals C07D213/61
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 239/48 : Two nitrogen atoms
• CPC Class Codes: C07D 241/22 : Benzenesulfonamido pyrazines
• CPC Class Codes: C07D 243/08 : not condensed with other rings
• CPC Class Codes: C07D 249/08 : 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 261/16 : Benzene-sulfonamido isoxazoles
• CPC Class Codes: C07D 277/04 : having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 285/06 : 1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
• CPC Class Codes: C07D 295/13 : to an acyclic saturated chain
• CPC Class Codes: C07D 295/192 : from aromatic carboxylic acids
• CPC Class Codes: C07D 295/26 : Sulfur atoms
• CPC Class Codes: C07D 307/14 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/22 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/24 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 317/58 : Radicals substituted by nitrogen atoms nitro radicals C07D317/52
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

Compounds of formula (I), pharmaceutically acceptable salts or in vivo hydrolysable esters thereof, wherein: Ring X is phenyl or a six membered heteroaryl ring containing one or two ring nitrogens where said nitrogens are optionally oxidised to form the N-oxide; R¹ and R² are substituents as defined within; R³ and R⁴ are defined within and are alkyl or halo alkyl or together form a halocycloalkyl ring; R⁵ is a substituent as defined within; Y—Z is a linking group as defined within; are useful in the production of a elevation of PDH activity in a warm-blooded animal such as a human being. Pharmaceutical compositions, methods and processes for preparation of compounds of formula (I) are described.

Claims

1. A compound of the formula (I):

wherein;

Ring X is phenyl;

R¹ and R² are independently as defined in (a) or (b);

R³ and R⁴ are as defined in (c) or (d);

R⁵ is as defined in (e) or (f);

Y—

Z is as defined in (g) or (h)

wherein;

(a) either R¹ and R² are each selected independently from hydrogen, C_1-3alkyl, pyridyl and phenyl which is unsubstituted or substituted by one or two substituents selected independently from C_1-4alkyl, C_1-4alkoxy, C_2-4alkenyloxy, hydroxy, halo and cyano,

or R¹ and R² together with the nitrogen atom to which they are attached form morpholino, thiomorpholino, piperidinyl, pyrrolidinyl or imidazolyl;

(b) either R¹ and R² are each selected independently from phenyl substituted by one or more P (wherein P is as defined hereinbelow), phenyl substituted by one or more groups selected from C_1-4alkyl, C_1-4alkoxy, C_2-4alkenyloxy, hydroxy, halo and cyano and additionally substituted by one or more groups selected from P, a heterocyclic group other than unsubstituted pyridyl which is optionally substituted on a ring carbon by one or more Q (wherein Q is as defined hereinbelow) and wherein if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinbelow), naphthyl optionally substituted by one or more Q, C_4-6alkyl, C_3-6cycloalkyl optionally substituted with one or more Q, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkyl substituted by one or more V (wherein V is as defined hereinbelow), R⁶T—

(wherein R⁶ and T are as defined hereinbelow) and R⁷C_1-6alkylT—

(where R⁷ is as defined hereinbelow),

or R¹ and R² together with the nitrogen atom to which they are attached form a heterocyclic group other than unsubstituted morpholino, unsubstituted thiomorpholino, unsubstituted piperidinyl, unsubstituted pyrrolidinyl or unsubstituted imidazolyl which is optionally substituted on a ring carbon by one or more Q (wherein Q is as defined hereinbelow) and wherein if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinbelow);

(c) either R³ and R⁴ are independently C_kalkyl optionally substituted by from 1 to 2k+1 atoms selected from fluoro and chloro wherein k is 1-3, provided that R³ and R⁴ are not both methyl;

or R³ and R⁴ together with the carbon atom to which they are attached, form a C_mcycloalkyl ring optionally substituted by from 1 to 2m−

2 fluorine atoms wherein m is 3-5;

(d) R³ and R⁴ are both methyl;

(e) R⁵ is C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxy, haloC_1-4alkoxy, cyano, nitro, C_2-4alkenyloxy or trifluoromethylthio;

(f) R⁵ is halo, hydroxy, amino, C_1-6alkylamino, (C_1-6alkyl)₂amino, C_1-6alkanoylamino, C_1-6alkanoyl(N—

C_1-6alkyl)amino, C_1-6alkylsulphonylamino, C_1-6alkylsulphonyl(N—

C_1-6alkyl)amino, thiol, C_1-6alkylsulphanyl, C_1-6alkylsulphinyl, C_1-6alkylsulphonyl, sulphamoyl, N-(C_1-6alkyl)aminosulphonyl, N-(C_1-66alkyl)₂aminosulphonyl, carboxy, carbamoyl, N-(C_1-6alkyl)carbamoyl, N-(C_1-6alkyl)₂carbamoyl, C_1-6alkoxycarbonyl, formyl, C_1-6alkanoyl, C_2-6alkenyl, C_2-6alkynyl, C_5-6alkyl, haloC_5-6alkyl, C_5-6alkoxy, haloC_5-6alkoxy or C_5-6alkenyloxy;

(g) Y—

Z is —

NHC(O)—

, —

OCH₂—

, —

SCH₂—

, —

NHCH₂—

or trans-vinylene;

(h) Y—

Z is —

NHC(S)—

;

R⁶ is selected from C_1-6alkyl (optionally substituted with one or more R⁸), C_3-6cycloalkyl optionally substituted with one or more R⁸, a heterocyclic group optionally substituted on a ring carbon by one or more R⁸ and if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinbelow), phenyl optionally substituted by one or more R⁸, naphthyl optionally substituted by one or more R⁸;

R⁷ is a heterocyclic group optionally substituted on a ring carbon by one or more R⁸ and if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinbelow), phenyl optionally substituted by one or more R⁸, naphthyl optionally substituted by one or more R⁸;

R⁸ is trifluoromethyl, C_1-6alkyl, halo, hydroxy, trifluoromethoxy, cyano, C_1-6alkoxy, formyl, C_1-6alkanoyl, C_1-6alkanoyloxy, amino, C_1-6alkylamino, (C_1-6alkyl)₂amino, C_1-6alkanoylamino, C_1-6alkanoyl(N—

C_1-6alkyl)amino, nitro, carboxy, carbamoyl, C_1-6alkoxycarbonyl, thiol, C_1-6alkylsulphanyl, C_1-6alkylsulphinyl, C_1-6alkylsulphonyl, sulphamoyl, N-(C_1-6alkyl)aminosulphonyl, N-(C_1-6alkyl)₂aminosulphonyl, carbamoylC_1-6alkyl, N-(C_1-6alkyl)carbamoylC_1-6alkyl, N-(C_1-6alkyl)₂carbamoyl-C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkoxyC ₁₆alkyl, phenylC_1-6alkyl or phenylC_1-6alkoxy;

P is selected from C_2-6alkyl-M—

substituted with one or more R⁹, C_2-6alkenyl-M—

optionally substituted with one or more R⁹, C_2-6alkynyl-M—

optionally substituted with one or more R⁹ (with the proviso that in the three previous groups R⁹ is not a substituent on the carbon atom attached to M), R¹⁰—

CH₂—

M—

, R¹¹—

M—

, thiol, C_1-6alkylsulphanyl, C_1-6alkylsulphinyl, C_1-6alkylsulphonyl, sulphamoyl, nitro, carboxy, C_1-6alkoxycarbonyl, amino, C_1-6alkylamino, (C_1-6alkyl)₂amino, carbamoyl, N-(C_1-6alkyl)carbamoyl, N-(C_1-6alkyl)₂carbamoyl, C_1-6alkanoylamino, C_1-6alkanoyl(N—

C_1-6alkyl)amino, trifluoromethyl, trifluoromethoxy, formyl, C_1-6alkanoyl, C_5-6alkyl, C_2-6alkenyl, C_2-6alkynyl N-(C_1-6alkyl)aminosulphonyl, hydroxymethyl, hydroxyacetyl, N-(C_1-6alkyl)₂aminosulphonyl, C_1-6alkanoylaminosulphonyl, C_1-6alkanoyl(N—

C_1-6alkyl)aminosulphonyl, C_1-6alkylsulphonylaminocarbonyl, C_1-6alkylsulphonyl(N—

C_1-6alkyl)aminocarbonyl, C_5-6alkoxy, C_5-6alkenyloxy, phenyl optionally substituted by one or more R⁸, naphthyl optionally substituted by one or more R⁸ and a heterocyclic group optionally substituted on a ring carbon by one or more R⁸ and if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinbelow);

Q is selected from any of the values defined for P, C_1-4alkyl, C_1-4alkoxy, C_2-4alkenyloxy, hydroxy, halo and cyano;

V is selected from any of the values defined for Q, phenyl optionally substituted by one or more Q, naphthyl optionally substituted by one or more Q, a heterocyclic group optionally substituted on a ring carbon by one or more Q and if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinbelow) and C_3-6cycloalkyl optionally substituted with one or more Q;

T is selected from —

O—

, —

C(O)—

, —

NH—

, —

N(N—

C_1-6alkyl)—

, —

C(O)NH—

, —

NHC(O)—

, —

C(O)N(N—

C_1-6alkyl)—

, —

N(N—

C_1-6alkyl)C(O)—

, —

SO₂—

, —

C(S)—

, —

C(S)NH—

, —

NHC(S)—

, —

C(S)N(N—

C_1-6alkyl)— and

—

N(N—

C_1-6alkyl)C(S)—

;

M is selected from —

O—

, —

N(R¹²)—

, —

C(O)—

, —

N(R¹²)C(O)—

, —

C(O)N(R¹²)—

, —

S(Q)_n—

, —

OC(O)—

, —

C(O)O—

, —

N(R¹²)C(O)O—

, —

OC(O)N(R¹²)—

, —

C(S)N(R¹²)—

, —

N(R¹²)C(S)—

, —

SO₂N(R¹²)—

, —

N(R¹²)SO₂—

, —

N(R¹²)C(O)N(R¹²)—

, —

N(R¹²)C(S)N(R¹²)—

, —

SO₂NHC(O)—

, —

SO₂N(R¹²)C(O)—

, —

C(O)NHSO₂— and

—

C(O)N(R¹²)SO₂—

, or M is a direct bond;

D is selected from C_1-6alkyl, C_1-6alkanoyl, C_1-6alkylsulphonyl, C_1-6alkoxycarbonyl, carbamoyl, N-(C_1-6alkyl)carbamoyl, N,N-(C_1-6alkyl)₂carbamoyl, benzoyl, (heterocyclic group)carbonyl, phenylsulphonyl, (heterocyclic group)sulphonyl, phenyl and a carbon linked heterocyclic group, and wherein any C_1-6alkyl group may be optionally substituted by one or more R⁹, and wherein any phenyl or heterocyclic group may be optionally substituted on a ring carbon by one or more groups selected from R⁸ and if a heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from E;

E is selected from C_1-6alkyl, C_1-6alkanoyl, C_1-6alkylsulphonyl, C_1-6alkoxycarbonyl, carbamoyl, N-(C_1-6alkyl)carbamoyl, N,N-(C_1-6alkyl)₂carbamoyl, C_1-6alkoxyC_1-6alkanoyl, phenylC_1-6alkyl, benzoyl, phenylC_1-6alkanoyl, phenylC_1-6alkoxycarbonyl and phenylsulphonyl;

R⁹ is selected from hydroxy, amino, C_1-6alkylamino, (C_1-6alkyl)₂amino, carboxy, C_1-6alkoxy, carbamoyl, N-(C_1-6alkyl)carbamoyl, N-(C_1-6alkyl)₂carbamoyl, formyl, sulphamoyl, N—

C_1-6alkylaminosulphonyl, N-(C_1-6alkyl)₂aminosulphonyl, C_1-6alkylsulphonylamino, C_1-6alkanoylamino, a heterocyclic group optionally substituted on a ring carbon by one or more R⁸ and if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinabove), phenyl optionally substituted by one or more R⁸, naphthyl optionally substituted by one or more R⁸, C_1-6alkylsulphanyl, C_1-6alkylsulphinyl and C_1-6alkylsulphonyl;

R¹⁰ is carboxy, carbamoyl, N-(C_1-6alkyl)carbamoyl, N-(C_1-6alkyl)₂carbamoyl, sulphamoyl, N-(C_1-6alkyl)aminosulphonyl, N-(C_1-6alkyl)₂aminosulphonyl, C_1-6alkylsulphanyl, C_{1 6}alkylsulphinyl, C_1-6alkylsulphonyl, C_1-6alkoxycarbonyl, C_1-6alkanoylamino, a heterocyclic group optionally substituted on a ring carbon by one or more R⁸ and if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinabove), phenyl optionally substituted by one or more R⁸ or naphthyl optionally substituted by one or more R⁸;

R¹¹ is a heterocyclic group optionally substituted on a ring carbon by one or more R⁸ and if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinabove), phenyl optionally substituted by one or more R⁸, C_3-6cycloalkyl optionally substituted by one or more R⁸, or naphthyl optionally substituted by one or more R⁸;

R¹² is hydrogen or C_1-6alkyl optionally substituted with R¹³ with the proviso that R¹³ is not a substituent on the carbon attached to the nitrogen atom of M;

R¹³ is halo, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkylamino, (C_1-6alkyl)₂amino, C_1-6alkanoylamino, C_1-6alkanoyl(N—

C_1-6alkyl)amino, C_1-6alkylsulphonylamino, C_1-6alkylsulphonyl(N—

C_1-6alkyl)amino, thiol, C_1-6alkylsulphanyl, C_1-6alkylsulphinyl, C_1-6alkylsulphonyl, sulphamoyl, N-(C_1-6alkyl)aminosulphonyl, N-(C_1-6alkyl)₂aminosulphonyl, carboxy, carbamoyl, N-(C_1-6alkyl)carbamoyl, N-(C_1-6alkyl)₂carbamoyl, C_1-6alkoxycarbonyl, C_1-6alkanoyl or formyl;

n is 0-2; and

wherein a heterocyclic group is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a —

CH₂—

group can optionally be replaced by a —

C(O)—

, a ring nitrogen atom may optionally bear a C_1-6alkyl group and form a quaternary compound or a ring nitrogen and/or sulphur atom may be optionally oxidised to form the N-oxide and or the S-oxides;

with the proviso that where R¹ and R² are both as defined in (a), R³ and R⁴ are both as defined in (c), R⁵ is as defined in (e) and Ring X is phenyl, then Y—

Z must be —

NHC(S)—

;

or a pharmaceutically acceptable salt thereof,

and provided said compound is not 4-(3-hydroxy-3-methyl-1-butynyl)-N-(3-methyl-2-pyridinyl)-benzenesulphonamide, N-{4-[N,N-bis-(sec-butyl)aminosulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide or N-{4-[N,N-bis-(iso-butyl)aminosulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide.

2. A compound of the formula (I) as claimed in claim 1 wherein R³ and R⁴ are independently C_kalkyl optionally substituted by from 1 to 2k+1 atoms selected from fluoro and chloro wherein k is 1-3.

3. A compound of the formula (I) as claimed in claim 1 or 2 wherein one of R³ and R⁴ is methyl and the other is trifluoromethyl.

4. A compound of the formula (I) as claimed in claim 1 or 2 wherein R⁵ is selected from halo, nitro, C_1-4alkyl, C_1-4alkoxy, C_2-4alkenyl;

C_2-4alkynyl, hydroxy, hydrogen, amino, carboxy and sulphamoyl.

5. A compound of the formula (I) as claimed in claim 1 or 2 wherein R⁵ is selected from fluoro and chloro.

6. A compound of the formula (I) as claimed in claim 1 or 2 wherein Y—

Z is —

NHC(O)—

.

7. A compound of the formula (I) as claimed in claim 1 or 2 wherein R¹ and R² are each independently selected from hydrogen, methyl, cyclopropyl, 4-hydroxycyclohexyl, 2-hydroxyethyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 4-(morpholinosulphonyl)phenyl, pyrid-3-yl, 2-carbamoylthien-3-yl, 2-chloropyrid-3-yl, 5-chloropyrid-2-yl, 5-methylpyrid-2-yl, pyrimid-2-yl, 4,6-dimethylpyrimid-2-yl or 5,6-dimethylpyrazin-2-yl;

or R¹ and R² together with the nitrogen atom to which they are attached form 4-hydroxypiperidinyl or 1-(hydroxyacetyl)piperazin-4-yl.

9. A pharmaceutical composition which comprises a compound of the formula (I) or (Ib) as claimed in claim 1 or 8 a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier.

10. A process for preparing a compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof, which process comprises:

reacting a compound of formula (XI);

 

where K is a leaving atom or group, and in which Y—

Z is OCH₂, SCH₂ or NHCH₂ or —

NHC(O)—

with an amine of formula R¹R²NH; and

thereafter if necessary;

i) converting a compound of the formula (I) into another compound of the formula (I);

ii) removing any protecting groups;

or

iii) forming a pharmaceutically acceptable salt.

11. A method of treating diabetes mellitus in a warm blooded animal in need thereof comprising administering to said animal an effective amount of a compound of formula (I) or (Ib) as claimed in claim 1 or 8.

8. A compound of formula (Ib):

wherein R^1b and R^2b are independently selected from;

i) hydrogen;

ii) C_1-6alkyl or C_3-6cycloalkyl optionally substituted with one or more C_1-6alkyl, C_1-6alkoxy, C_2-6alkenyloxy, hydroxy, halo, cyano, C_1-6alkylsulphanyl, C_1-6alkylsulphinyl, C_1-6alkylsulphonyl, sulphamoyl, carboxy, C_1-6alkoxycarbonyl, amino, C_1-6alkylamino, (C_1-6alkyl)₂amino, carbamoyl, N-(C_1-6alkyl)carbamoyl, N-(C_1-6alkyl)₂carbamoyl, C_1-6alkanoylamino, C_1-6alkanoyl(N—

C_1-6alkyl)amino, C_1-6alkanoyl, C_2-6alkenyl, C_2-6alkynyl, N-(C_1-6alkyl)aminosulphonyl, hydroxymethyl, hydroxyacetyl or N-(C_1-6alkyl)₂aminosulphonyl;

iii) a heterocyclic group selected from pyridyl, pyrimidyl, pyridazinyl or pyrazinyl, wherein said heterocyclic group is optionally substituted with one or more C_1-6alkyl, C_1-6alkoxy, C_2-6alkenyloxy, hydroxy, halo, cyano, C_1-6alkylsulphanyl, C_1-6alkylsulphinyl, C_1-6alkylsulphonyl, sulphamoyl, carboxy, C1-6alkoxycarbonyl, amino, C_1-6alkylamino, (C_1-6alkyl)₂amino, carbamoyl, N-(C_1-6alkyl)carbamoyl, N-(C_1-6alkyl)₂carbamoyl, C_1-6alkanoylamino, C_1-6alkanoyl(N—

C_1-6alkyl)amino, trifluoromethyl, trifluoromethoxy, C_1-6alkanoyl, C_2-6alkenyl, C_2-6alkynyl, N-(C_1-6alkyl)aminosulphonyl, hydroxymethyl, hydroxyacetyl or N-(C_1-6alkyl)₂aminosulphonyl;

or R^1b and R^2b together with the nitrogen atom to which they are attached form piperidinyl or piperazinyl;

wherein said piperidinyl and piperazinyl may be optionally substituted on a ring carbon by one or more groups selected from C_1-6alkyl, C_1-6alkoxy, C_2-6alkenyloxy, hydroxy, halo, cyano, C_1-6alkylsulphanyl, C_1-6alkylsulphinyl, C_1-6alkylsulphonyl, sulphamoyl, carboxy, C_1-6alkoxycarbonyl, amino, C_1-6alkylamino, (C_1-6alkyl)₂amino, carbamoyl, N-(C_1-6alkyl)carbamoyl, N-(C_1-6alkyl)₂carbamoyl, C_1-6alkanoylamino, C_1-6alkanoyl(N—

C_1-6alkyl)amino, C_1-6alkanoyl, C_2-6alkenyl, C_2-6alkynyl, N-(C_1-6alkyl)aminosulphonyl, hydroxymethyl, hydroxyacetyl or N-(C_1-6alkyl)₂aminosulphonyl; and

said piperazinyl may be optionally substituted on the ring nitrogen by a group selected from C_1-6alkanoyl, C_1-6alkylsulphonyl, C_1-6alkoxycarbonyl, carbamoyl, N-(C_1-6alkyl)carbamoyl and N,N-(C_1-6alkyl)₂carbamoyl; and

wherein any C_1-6alkyl group may be optionally substituted by one or more groups selected from hydroxy, amino, C_1-6alkylamino, (C_1-6alkyl)₂amino, carboxy, C_1-6alkoxy, carbamoyl, N-(C_1-6alkyl)carbamoyl, N-(C_1-6alkyl)₂carbamoyl, sulphamoyl, N—

C_1-6alkylaminosulphonyl, N-(C_1-6alkyl)₂aminosulphonyl, C_1-6alkylsulphonylamino, C_1-6alkanoylamino, C_1-6alkylsulphanyl, C_1-6alkylsulphinyl and C_1-6alkylsulphonyl,

and pharmaceutically acceptable salts thereof.