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Title:
SPECIFIC GLUCOCORTICOSTEROID COMPOUND HAVING ANTI- INFLAMMATORY ACTIVITY
Document Type and Number:
WIPO Patent Application WO/2005/005451
Kind Code:
A1
Abstract:
A compound of formula (I): (I) wherein X represents O or S; R1 represents C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkylmethyl or C3-8 cycloalkenyl any of which optionally may be substituted by one or more methyl groups or halogen atoms or R1 represents aryl, substituted aryl, heteroaryl or substituted heteroaryl; R2 represents hydrogen, methyl, which may be in either the &agr or β configuration, or methylene; R3 and R4 are the same or different and each independently represents hydrogen, halogen or a methyl group; and represents a single or a double bond; or a physiologically acceptable salt or solvate thereof.

Inventors:
Biggadike, Keith (GlaxoSmithKline, Gunnels Wood Road, Stevenage Hertfordshire SG1 2NY, GB)
John, Matthew Peter (GlaxoSmithKline, Gunnels Wood Road, Stevenage Hertfordshire SG1 2NY, GB)
Needham, Deborah (GlaxoSmithKline, Gunnels Wood Road, Stevenage Hertfordshire SG1 2NY, GB)
Application Number:
PCT/EP2004/007819
Publication Date:
January 20, 2005
Filing Date:
July 09, 2004
Export Citation:
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Assignee:
GLAXO GROUP LIMITED (Glaxo Wellcome House, Berkeley Avenue, Greenford Middlesex UB6 0NN, GB)
Biggadike, Keith (GlaxoSmithKline, Gunnels Wood Road, Stevenage Hertfordshire SG1 2NY, GB)
John, Matthew Peter (GlaxoSmithKline, Gunnels Wood Road, Stevenage Hertfordshire SG1 2NY, GB)
Needham, Deborah (GlaxoSmithKline, Gunnels Wood Road, Stevenage Hertfordshire SG1 2NY, GB)
International Classes:
A61P5/44; C07D215/26; C07D233/54; C07D451/02; C07J1/00; C07J3/00; (IPC1-7): C07J3/00; A61K31/56; A61P5/44; C07D239/20
Domestic Patent References:
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WO1989003390A1
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Foreign References:
GB1514476A
US3856828A
GB2079755A
GB2137206A
GB1384372A
GB1514476A
US3856828A
GB2079755A
GB2137206A
GB1384372A
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EP0314867W
EP2004005494W2004-05-19
USPP48798103P2003-07-17
USPP51100903P2003-10-14
Other References:
UENO H ET AL: "Synthesis and evaluation of antiinflammatory activities of a series of corticosteroid 17.alpha.-esters containing a functional group" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 34, no. 8, 1 August 1991 (1991-08-01), pages 2468-2473, XP002086576 ISSN: 0022-2623
UENO H ET AL.: 'Sythethis and evaluation of anti-inflammatory activities of a series of corticosteroid 17.alpha.-esters containing a functional group' J MED CHEM vol. 34, no. 8, 01 August 1991, pages 2468 - 2473
HOFGEN, N. ET AL. 15TH EFMC INT SYMP MED CHEM 06 September 1998,
LANDELLS, L.J. ET AL. EUR RESP J [ANNU CONG EUR RESP SOC vol. 12, no. 28, 19 September 1998,
TANABE SEIYAKU; FUJI, K. ET AL. J PHARMACOL EXP THER vol. 284, no. 1, 1998, page 162
G. H. PHILLIPPS ET AL. JOURNAL OF MEDICINAL CHEMISTRY vol. 37, 1994, pages 3717 - 3729
K.P.RAY ET AL. BIOCHEM J. vol. 328, 1997, pages 707 - 715
R.J.H. AUSTIN ET AL. EUR RESP J. vol. 20, 2002, pages 1386 - 1392
DI LORENZO ET AL. CANCER RESEARCH vol. 51, 1991, pages 4470 - 4475
Attorney, Agent or Firm:
Pritchard, Judith (GlaxoSmithKline, Corporate Intellectual Property 980 Great West Road, Brentford Middlesex TW8 9GS, GB)
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Claims:
CLAIMS
1. A compound of formula (I) : wherein X represents O or S; Ri represents Ci. alkyl, C38 cycloalkyl, C38 cycloalkylmethyl or C38 cycloalkenyl any of which optionally may be substituted by one or more methyl groups or halogen atoms or Ri represents aryl, substituted aryl, heteroaryl or substituted heteroaryl ; R2 represents hydrogen, methyl, which may be in either the a or (3 configuration, or methylene ; R3 and R4 are the same or different and each independently represents hydrogen, halogen or a methyl group ; and # represents a single or a double bond; or a physiologically acceptable salt or solvate thereof.
2. A compound as claimed in claim 1 wherein X represents 0.
3. A compound as claimed in claim 1 or claim 2 wherein Ra represents a C36 cycloalkyl group optionally substituted by one or more methyl or chlorine groups.
4. A compound as claimed in any one of claims 1 to 3 wherein R, represents 2,2, 3, 3tetramethylcyclopropyl.
5. A compound as claimed in any one of the preceding claims wherein R2 represents methyl in the aconfiguration.
6. A compound as claimed in any one of the preceding claims wherein R3 and R4 are both fluorine.
7. A compound as claimed in anyone of the preceding claims wherein ~~~~~ represents a double bond.
8. A compound as claimed in any one of the preceding claims which is 6α, 9αDifluoro11ßhydroxy16αmethyl3oxo17α(2, 2,3, 3 tetramethycyclopropylcarbonyl) oxyandrosta1, 4diene17 (3carbothioic acid S cyanomethyl ester; 17α(4[(Diethylamino)sulphonyl]benzoyl)oxy6α,9αdifluoro11ßhydroxy16α methyl3oxoandrosta1, 4diene17pcarbothioic acid Scyanomethyl ester; 17a (5Chloro4methoxythiophene3carbonyl) oxy6a, 9adifluoro1 1 Phydroxy16a methyl3oxoandrosta1, 4diene17ßcarbothioic acid Scyanomethyl ester; 6α,9αDifluoro11ßhydroxy16αmethyl3oxo17α(2,2 3,3 tetramethycyclopropylcarbonyl) oxyandrosta1, 4diene17ßcarboxylic acid cyanomethyl ester; 17α(Cyclohexylcarbonyl)oxy6α,9αdifluoro11ßhydroxy16αmethyl3oxo androsta1, 4diene17pcarboxylic acid cyanomethyl ester; 6a, 9aDifluoro17a(2, 6difluorobenzoyl) oxy11 ßhydroxy16amethyl3oxo androsta1, 4diene17ßcarboxylic acid cyanomethyl ester ; 6a, 9αDifluoro11ßhydroxy17α(4methoxybenzoyl)oxy16αmethyl3oxo androsta1, 4diene17pcarboxylic acid cyanomethyl ester ; <BR> <BR> <BR> <BR> 17α(4Cyanobenzoyl)oxy6α,9αdifluoro11ßhydroxy16αmethyl3oxoandrosta 1, 4diene17ßcarboxylic acid cyanomethyl ester ; <BR> <BR> <BR> <BR> 17α(Cyclopentylmethylcarbonyl)oxy6α,9αdifluoro11ßhydroxy16αmethyl3oxo androsta1, 4diene17ßcarboxylic acid cyanomethyl ester ; 6a, 9αDifluoro17α(3,3dimethylbutanoyl)oxy11ßhydroxy16αmethyl3oxo androsta1, 4diene17ßcarboxylic acid cyanomethyl ester ; 6a, 9aDifluoro11 ßhydroxy17a(2isopropyl1, 3thiazole4carbonyl) oxy160c methyl3oxoandrosta1, 4diene17pcarboxylic acid cyanomethyl ester ; 6a, 9aDifluoro11 ßhydroxy16ccmethyl3oxo17a(quinoline2carbonyl) oxy androsta1, 4diene17ßcarboxylic acid cyanomethyl ester; 6a, 9aDifluoro11 1ßhydroxy16αmethyl3oxo17α(5trifluoromethylfuran2 carbon) oxyandrosta1,4diene17ßcarboxylic acid cyanomethyl ester ; 6oc, 9aDifluoro11 ihydroxy16amethyl17a (5methylsulphonylthiophene2 carbonyl) oxy3oxoandrosta1, 4diene1 (3carboxylic acid cyanomethyl ester; 6a, 9αDifluoro11ßhydroxy16αmethyl 17α(5methylthiothiophene2 carbonyl) oxy3oxoandrosta1, 4diene17pcarboxylic acid cyanomethyl ester; 6a, 9αDifluoro17α(5ethylisoxazole3carbonyl)oxy11ßhydroxy16αmethyl3 oxoandrosta1, 4diene17ßcarboxylic acid cyanomethyl ester; 9αFluoro11ßhydroxy16ßmethyl3oxo17α(2, 2,3, 3 tetramethylcyclopropylcarbonyl) oxyandrosta1, 4diene17pcarboxylic acid cyanomethyl ester. 6a, 9aDifluoro11 ihydroxy16amethyl3oxo17a (2, 2,3, 3 tetramethycyclopropylcarbonyl) oxyandrost4ene17pcarboxylic acid cyanomethyl ester; <BR> <BR> <BR> 17a (5Chloro4methoxythiophene3carbonyl) oxy6a, 9adifluoro11 hydroxy16a methyl3oxoandrosta1, 4diene17ßcarboxylic acid cyanomethyl ester; 17a (2, 2Dichloro3, 3dimethylclopropylcarbonyl) oxy6a, 9αdifluoro11ßhydroxy 16ccmethyl3oxoandrosta1, 4diene17pcarboxylic acid cyanomethyl ester; 177a (2, 2Dichloro3, 3dimethylclopropylcarbonyl) oxy6a, 9cdifluoro11 (3hydroxy 16αmethyl3oxoandrosta1, 4diene17pcarbothioic acid Scyanomethyl ester ; 17α(Cyclohexylcarbonyl)oxy6α,9αdifluoro11ßhydroxy16αmethyl3oxo androsta1, 4diene17pcarbothioic acid Scyanomethyl ester; 6a, 9αDifluoro11ßhydroxy16αmethyl 17α(5methylsulphonylthiophene2 carbonyl) oxy3oxoandrosta1, 4diene17 (3carbothioicacid Scyanomethyt ester ; 6cc, 9αDifluoro1 1ßhydroxy16αmethyl3oxo17α(5trifluoromethylfuran2 carbonyl) oxyandrosta1, 4diene17ßcarbothioic acid Scyanomethyl ester ; or <BR> <BR> <BR> 6c, 9αDifluoro17α(3(difluoromethylthio)benzoyl)oxy11ßhydroxy16αmethyl3<BR> <BR> <BR> <BR> oxoandrosta1, 4diene17pcarbothioic acid Scyanomethyl ester.
9. A compound as claimed in claim 8 which is 6oc, 9αDifluoro11ßhydroxy16αmethyl3oxo17α(2, 2,3, 3 tetramethycyclopropylcarbonyl)oxyandrosta1,4diene17ßcarbothioic acid S cyanomethyl ester; 6oc, 9aDifluoro11 3hydroxy16amethyl3oxo17a (2, 2,3, 3 tetramethycyclopropylcarbonyl) oxyandrosta1, 4diene17pcarboxylic acid cyanomethyl ester ; 9αFluroo11ßhydroxy16ßmethyl3oxo17α(2, 2,3, 3 tetramethylcyclopropylcarbonyl) oxyandrosta1, 4diene17pcarboxylic acid cyanomethyl ester; 177a (Cyclohexylcarbonyl) oxy6a, 9adifluoro11 3hydroxy16amethyl3oxo androsta1, 4diene17 (3carboxylic acid cyanomethyl ester; <BR> <BR> <BR> 17a (Cyclopentylmethylcarbonyl) oxy6a, 9adifluoro11 hydroxy16amethyl3oxo androsta1, 4diene17ßcarboxylic acid cyanomethyl ester; 6a, 9αDifluoro17α(3,3dimethylbutanoyl)oxy11ßhydroxy16αmethyl3oxo androsta1, 4diene17pcarboxylic acid cyanomethyl ester; 6a, 9aDifluoro17a (3 (difluoromethylthio) benzoyl) oxy11 ihydroxy16amethyl3 oxoandrosta1, 4diene17ßcarbothioic acid Scyanomethyl ester ; 17a (Cyclohexylcarbonyl) oxy6a, 9adifluoro11 ihydroxy16amethyl3oxo androsta1, 4diene17pcarbothioic acid Scyanomethyl ester; <BR> <BR> <BR> 6a, 9aDifluoro17a (5ethylisoxazole3carbonyl) oxy11 ihydroxy16a,methyl3 oxoandrosta1, 4diene17ßcarboxylic acid cyanomethyl ester; 6cc, 9αDifluoro11ßhydroxy16αmethyl 17α(5methylthiothiophene2 carbonyl) oxy3oxoandrosta1, 4diene17pcarboxylic acid cyanomethyl ester; 6α,9αDifluoro11ßhydroxy17α(2isopropyl1,3thiazole4carbonyl)oxy16α methyl3oxoandrosta1, 4diene17ßcarboxylic acid cyanomethyl ester ; <BR> <BR> <BR> 17α(2,2Dichloro3,3dimethylclopropylcarbonyl)oxy6α,9αdifluoro11ßhydroxy 16amethyl3oxoandrosta1, 4diene17ßcarbothioic acid Scyanomethyl ester ; or <BR> <BR> <BR> 17α(2,2Dichloro3,3dimethylclopropylcarbonyl)oxy6α,9αdifluoro11ßhydroxy<BR> <BR> <BR> <BR> 16amethyl3oxoandrosta1, 4diene17ßcarboxylic acid cyanomethyl ester.
10. A compound as claimed in claim 9 which is <BR> <BR> <BR> 17α(2,2Dichloro3,3dimethylclopropylcarbonyl)oxy6α,9αdifluoro11ßhydroxy<BR> <BR> <BR> <BR> 16αmethyl3oxoandrosta1,4diene17ßcarboxylic acid cyanomethyl ester; 6α,9αDifluoro11ßhydroxy16αmethyl3oxo17α(2,2, 3, 3 tetramethycyclopropylcarbonyl)oxyandrosta1,4diene17ßcarbothioic acid S cyanomethyl ester; or 6a, 9αDifluoro11ßhydroxy16αmethyl3oxo17α(2, 2,3, 3 tetramethycyclopropylcarbonyl) oxyandrosta1, 4diene17 (3carboxylic acid cyanomethyl ester.
11. A compound as claimed in claim 10 which is 6cc, 9aDifluoro11 ihydroxy16amethyl3oxo17a (2, 2,3, 3 tetramethycyclopropylcarbonyl) oxyandrosta1, 4diene17pcarboxylic acid cyanomethyl ester.
12. A compound of formula (I) as defined in any one of claims 1 to 11 or a physiologically acceptable solvate thereof for use in veterinary or human medicine.
13. Use of a compound of formula (I) as defined in any one of claims 1 to 11 or a physiologically acceptable solvate thereof for the manufacture of a medicament for the treatment of inflammatory and/or allergic conditions.
14. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 11 or a physiologically acceptable solvate thereof together, if desirable, in admixture with one or more physiologically acceptable diluents or carriers.
15. A pharmaceutical aerosol formulation comprising a compound of formula (I) as defined in any one of claims 1 to 11 or a physiologically acceptable solvate thereof, and a fluorocarbon or hydrogencontaining chlorofluoro carbon as propellant, optionally in combination with a surfactant and/or a solvent.
16. A pharmaceutical composition according to claim 15 which further comprises another therapeutical active agent.
17. A pharmaceutical composition according to claim 16 in which said another therapeutically active agent is a ß2adrenoreceptor agonist.
18. A method for the treatment of a human or animal subject with an anti inflammatory and/or allergic condition, which method comprises administering to said human or anima) subject an effective amount of a compound of formula (l) as defined in any one of claims 1 to 11 or a physiologically acceptable solvate thereof.
19. A compound which is 17α(4[(Diethylamino)sulphonyl]benzoyl)oxy6α,9αdifluoro11ßhydroxy 16amethyl3oxoandrosta1, 4diene17ßcarbothioic acid 6a, 9aDifluoro17a (2, 6difluorobenzoyl) oxy11 ihydroxy16amethyl3oxo androsta1, 4diene17 (3carboxylic acid 6a, 9αDifluoro11ßhydroxy17α(4methoxybenzoyl)oxy16αmethylo3oxo androsta1, 4diene17ßcarboxylic acid <BR> <BR> 17a (4Cyanobenzoyl) oxy6a, 9adifluoro11 phydroxy16amethyl3oxoandrosta 1, 4diene17ßcarboxylic acid 6a, 9aDifluoro17a (3, 3dimethylbutanoyl) oxy11 ihydroxy16amethyl3oxo androsta1, 4diene17pcarboxylic acid 6a, 9a,Difluoro11 3hydroxy17a (2isopropyl1, 3thiazole4carbonyl) oxy16a methyl3oxoandrosta1, 4diene17ßcarboxylic acid 6a, 9aDifluoro11 ihydroxy16amethyl3oxo17a (quinoline2carbonyl) oxy androsta1, 4diene17ßcarboxylic acid 6a, 9αDifluoro11ßhydroxy16αmethyl3oxo17α(5trifluoromethylfuran2 carbonyl) oxyandrosta1, 4diene17ßcarboxylic acid <BR> <BR> 6oc, 9αDifluoro11ßhydroxy16αmethyl 17α(5methylsulphonylthiophene2 carbonyl) oxy3oxoandrosta1, 4diene17ßcarboxylic acid 6a, 9αDifluoro11ßhydroxy16αmethyl 17α(5methylthiothiophene2 carbonyl) oxy3oxoandrosta1, 4diene17pcarboxylic acid 6a, 9αDifluoro17α(5ethylisoxazole3carbonyl)oxy11ßhydroxy16αmethyl3 <BR> <BR> oxoandrosta1, 4diene17pcarboxylic acid <BR> <BR> 17a (5Chloro4methoxythiophene3carbonyl) oxy6a, 9adifluoro11 3hydroxy16a <BR> <BR> methyl3oxoandrosta1, 4diene17ßcarboxylic acid <BR> <BR> 17α(2,2Dichloro3,3dimethylclopropylcarbonyl)oxy6α,9αdifluoro11ßhydroxy 16amethyl3oxoandrosta1, 4diene17ßcarboxylic acid <BR> <BR> 17α(2,2Dichloro3,3dimethylclopropylcarbonyl)oxy6α,9αdifluoro11ßhydroxy<BR> <BR> 16αmethyl3oxoandrosta1,4diene17ßcarbothioic acid 6a, 9αDifluoro11ßhydroxy16αmethyl <BR> <BR> 17α(5methylsulphonylthiophene2carbonyl)oxy3oxoandrosta1,4diene17ß carbothioic acid 6oc, 9aDifluoro11 ßhydroxy16αmethyl3oxo17α(5trifluoromethylfuran2 carbonyl) oxyandrosta1, 4diene17pcarbothioic acid, or <BR> <BR> 6cc, 9αDifluoro17α(3(difluoromethylthio)benzoyl)oxy11ßhydroxy16αmethyl3 oxoandrosta1, 4diene17pcarbothioicacid.
20. A compound of formula (IV) : 2, 3dimethyl1[(2, 2,3, 3tetramethylcyclopropyl) carbonyl]1Himidazol3ium chloride.
21. A process for preparing a compound of formula (II) where R1 represents 2,2, 3, 3tetramethyl cyclopropyl and R2, R3, R4, X and are as defined in any one of claims 1 to 7 which process comprises reaction of the 1, 2dimethyl1 Himidazolium ester of 2,2, 3, 3tetramethylcyclopropane carboxylic acid (IV) with the corresponding 17αhydroxyl derivative of formula (III).
22. A process as claimed in claim 21 in which X represents 0.
Description:
SPECIFIC GLUCOCORTICOSTEROID COMPOUND HAVING ANTI-INFLAMMATORY ACTIVITY The present invention relates to compounds which are glucocorticoid receptor agonists of the androstane series and to processes for their preparation. The present invention also relates to pharmaceutical formulations containing the compounds and to therapeutic uses thereof, particularly for the treatment of inflammatory and allergic conditions.

Glucocorticosteroids which have anti-inflammatory properties are known and are widely used for the treatment of inflammatory disorders or diseases such as asthma and rhinitis. However, we have identified a novel series of glucocorticosteroids.

Thus, according to one aspect of the invention, there is provided a compound of formula (I) wherein X represents 0 or S; Ri represents C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkylmethyl or C3-8 cycloalkenyl any of which optionally may be substituted by one or more methyl groups or halogen atoms or R, represents aryl, substituted aryl, heteroaryl or substituted heteroaryl ; R2 represents hydrogen, methyl, which may be in either the a or P configuration, or methylene ; R3 and R4 are the same or different and each independently represents hydrogen, halogen or a methyl group; and-----represents a single or a double bond; or a physiologically acceptable salt or solvate thereof.

Examples of solvates include hydrates.

References hereinafter to a compound according to the invention includes both compounds of formula (I) and salts and solvates thereof.

It will be appreciated that the invention includes within its scope all stereoisomers of the compounds of formula (I) and mixtures thereof.

Preferably, the absolute stereochemistry will be as shown in the representation of compounds of formula (I).

Preferably, X represents 0.

Preferred examples of C1 6 alkyl groups that Ri may represent include 2, 2- dimethyl propyl.

Preferred examples of C3-8 cycloalkyl groups that Ri may represent include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and substituted derivatives such as methylcyclopropyl (eg 1-methylcyclopropyl), dichlorodimethylcyclopropyl (eg 2,2- dichloro-3, 3-dimethylcyclopropyl) and tetramethylcyclopropyl (eg 2,2, 3,3- tetramethylcyclopropyl).

Preferred examples of Cs-s cycloalkylmethyl groups that Ri may represent include cyclopentylmethyl.

Preferred examples of C3-8 cycloalkenyl groups that R1 may represent include alkenyl groups containing 1 or more double bonds (not being aromatic groups) such as cyclohexenyl eg cyclohex-2, 3-enyl.

In some embodiments it is preferred that Ri represents a substituted aryl group.

Preferred examples of substituted aryl groups that Ri may represent include 4- (diethylamino) sulphonylphenyl, 2, 6-difluorophenyl, 4-methoxyphenyl, 3-difluoromethylthiophenyl and 4-cyanophenyl.

Preferred examples of heteroaryl groups that Ri may represent include quinoline-2-yl.

Preferred examples of substituted heteroaryl groups that Ri may represent include 5-chloro-4-methoxy-thiophene-3-yl, 2-isopropyl-1, 3-thiazol-4-yl, 5-trifluoromethylfuran-2-yl, 5-methylsulphonyl-thiophene-2-yl, 5-methylthio-thiophene-2-yl and 5-ethyl-isoxazol-3-yl.

We prefer Ri to represent C3-8 cycloalkyl optionally substituted by one or more methyl and/or halogen groups. We particularly prefer Ri to represent C3-6 cycloalkyl optionally substituted by one or more methyl or chlorine groups.

Most preferred groups that Ri may represent include tetramethylcyclopropyl, dichlorodimethylcyclopropyl, cyclohexyl, and cyclopentylmethyl, especially 2,2, 3,3- tetramethylcyclopropyl and 2, 2-dichloro-3, 3-dimethylcyclopropyl, most especially 2,2, 3, 3-tetramethylcyclopropyl.

We prefer R2 to represent methyl, especially methyl in the a configuration.

Compounds of formula (I) in which R3 and R4, which can be the same or different, each represents hydrogen, methyl, fluorine or chlorine, particularly hydrogen or fluorine are preferred. Especially preferred are compounds in which R3 and R4 are both fluorine.

Preferably, # represents a double bond.

It is to be understood that the present invention covers all combinations of particularly and preferred groups referred to hereinabove.

Preferred compounds of formula (I) include : 6α, 9a-Difluoro-11 (3-hydroxy-16oc-methyl-3-oxo-17a,- (2, 2,3, 3- tetramethycyclopropylcarbonyl) oxy-androsta-1, 4-diene-17p-carbothioic acid S-cyanomethyl ester ; 17α-(4-[(Diethylamino)sulphonyl]benzoyl)oxy-6α,9α-difluor o-11ß-hydroxy-16α- methyl-3-oxo-androsta-1, 4-diene-17p-carbothioic acid S-cyanomethyl ester;

17a- (5-Chloro-4-methoxy-thiophene-3-carbonyl) oxy-6a, 9a-difluoro-11 i-hydroxy-16a- methyl-3-oxo-androsta-1, 4-diene-17ß-carbothioic acid S-cyanomethyl ester; 6a, 9a-Difluoro-11 ß-hydroxy-16a-methyl-3-oxo-17a-(2, 2,3, 3- tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17ß-ca rboxylic acid cyanomethyl ester; 17α-(Cyclohexylcarbonyl)oxy-6α,9α-difluoro-11ß-hydroxy-1 6α-methyl-3-oxo- androsta-1, 4-diene-17ß-carboxylic acid cyanomethyl ester; 6a, 9a-Difluoro-17a-(2, 6-difluorobenzoyl) oxy-11 ß-hydroxy-16a-methyl-3-oxo- androsta-1, 4-diene-17ß-carboxylic acid cyanomethyl ester; 6a, 9α-Difluoro-11ß-hydroxy-17α-(4-methoxybenzoyl)oxy-16α-me thyl-3-oxo- androsta-1, 4-diene-17p-carboxylic acid cyanomethyl ester; <BR> <BR> 17a-(4-Cyanobenzoyl) oxy-6a, 9a-difluoro-11 ß-hydroxy-16a-methyl-3-oxo-androsta- 1, 4-diene-17p-carboxylic acid cyanomethyl ester; <BR> <BR> 17a-(Cyclopentylmethylcarbonyl) oxy-6a, 9a-difluoro-11 ß-hydroxy-16a-methyl-3-oxo- androsta-1, 4-diene-17p-carboxylic acid cyanomethyl ester; 6α,9α-Difluoro-17α-(3,3-dimethylbutanoyl)oxy-11ß-hydroxy -16α-methyl-3-oxo- androsta-1, 4-diene-17p-carboxylic acid cyanomethyl ester; 6cc, 9α-Difluoro-11ß-hydroxy-17α-(2-isopropyl-1,3-thiazole-4-c arbonyl)oxy-16α- methyl-3-oxo-androsta-1, 4-diene-17p-carboxylic acid cyanomethyl ester; 6α,9α-Difluoro-11ß-hydroxy-16α-methyl-3-oxo-17α-(quinol ine-2-carbonyl)oxy- androsta-1, 4-diene-17p-carboxylic acid cyanomethyl ester; 6a, 9α-Difluoro-11ß-hydroxy-16α-methyl-3-oxo-17α-(5-trifluor omethyl-furan-2- carbonyl) oxy-androsta-1,4-diene-17ß-carboxylic acid cyanomethyl ester ; 6oc, 9α-Difluoro-11ß-hydroxy-16α-methyl-17α-(5-methylsulphony l-thiophene-2- carbonyl) oxy-3-oxo-androsta-1,4-diene-17ß-carboxylic acid cyanomethyl ester; 6a, 9α-Difluoro-11ß-hydroxy-16α-methyl -17α-(5-methylthio-thiophene-2- carbonyl) oxy-3-oxo-androsta-1, 4-diene-17ß-carboxylic acid cyanomethyl ester ; 6α,9α-Difluoro-17α-(5-ethyl-isoxazole-3-carbonyl)oxy-11ß -hydroxy-16α-methyl-3- oxo-androsta-1, 4-diene-17ß-carboxylic acid cyanomethyl ester ; 9α-Fluoro-11ß-hydroxy-16ß-methyl-3-oxo-17α-(2, 2,3, 3- tetramethylcyclopropylcarbonyl) oxy-androsta-1, 4-diene-17p-carboxylic acid cyanomethyl ester.

6ec, 9a-Difluoro-11 P-hydroxy-16a-methyl-3-oxo-177c- (2, 2,3, 3- tetramethycyclopropylcarbonyl) oxy-androst-4-ene-17ß-carboxylic acid cyanomethyl ester;

17a- (5-Chloro-4-methoxy-thiophene-3-carbonyl) oxy-6a, 9a-difluoro-11 (3-hydroxy-16a- methyl-3-oxo-androsta-1, 4-diene-17p-carboxylic acid cyanomethyl ester; 17α-(2,2-Dichloro-3,3-dimethylclopropylcarbonyl)oxy-6α,9α -difluoro-11ß-hydroxy- 16a-methyl-3-oxo-androsta-1, 4-diene-17p-carboxylic acid cyanomethyl ester; 17a- (2, 2-Dichloro-3, 3-dimethylclopropylcarbonyl) oxy-6a, 9α-difluoro-11ß-hydroxy- 16α-methyl-3-oxo-androsta-1, 4-diene-17ß-carbothioic acid S-cyanomethyl ester; 17a- (Cyclohexylcarbonyl) oxy-6a, 9a-difluoro-11 3-hydroxy-16cc-methyl-3-oxo- androsta-1, 4-diene-17 (3-carbothioic acid S-cyanomethyl ester; 6a, 9a-Difluoro-11 i-hydroxy-16a-methyl-17a- (5-methylsulphonyl-thiophene-2- carbonyl) oxy-3-oxo-androsta-1, 4-diene-17ß-carbothioic acid S- cyanomethyl ester; 6α, 9c-Difluoro-11 i-hydroxy-16a-methyl-3-oxo-17a- (5-trifluoromethyl-furan-2- carbonyl) oxy-androsta-1, 4-diene-17ß-carbothioic acid S-cyanomethyl ester; and 6a, 9a-Difluoro-1 7a- (3- (difluoromethylthio) benzoyl) oxy-1 1 P-hydroxy-1 6a-methyl-3- oxo-androsta-1, 4-diene-17ß-carbothioic acid S-cyanomethyl ester; Particularly preferred compounds are: 6a, 9α-Difluoro-11ß-hydroxy-16α-methyl-3-oxo-17α-(2, 2,3, 3- tetramethycyclopropylcarbonyl) oxy-androsta-1,4-diene-17ß-carbothioic acid S-cyanomethyl ester ; 6a, 9a-Difluoro-11 ß-hydroxy-16α-methyl-3-oxo-17α-(2,2, 3,3- tetramethycyclopropylcarbonyl) oxy-androsta-1,4-diene-17ß-carboxylic acid cyanomethyl ester ; 9a-Fluoro-1 I P-hydroxy-I 6p-methyl-3-oxo-1 7a- (2, 2,3, 3- tetramethylcyclopropylcarbonyl) oxy-androsta-1,4-diene-17ß-carboxylic acid cyanomethyl ester ; 17α-(Cyclohexylcarbonyl)oxy-6α,9α-difluoro-11ß-hydroxy-1 6α-methyl-3-ox- androsta-1,4-diene-17ß-carboxylic acid cyanomethyl ester; <BR> <BR> <BR> <BR> 17α-(Cyclopentylmethylcarbonyl)oxy-6α,9α-difluoro-11ß-hy droxy-16α-methyl-3-oxo- androsta-1, 4-diene-17ß-carboxylic acid cyanomethyl ester; 6α,9α-Difluoro-17α-(3,3-dimethylbutanoyl)oxy-11ß-hydroxy -16α-methyl-3-oxo- androsta-1, 4-diene-17 (3-carboxylic acid cyanomethyl ester;

6α, 9a-Difluoro-17a- (3- (difluoromethylthio) benzoyl) oxy-11 3-hydroxy-16a-methyl-3- oxo-androsta-1, 4-diene-17ß-carbothioic acid S-cyanomethyl ester; 17α-(Cyclohexylcarbonyl)oxy-6α,9α-difluoro-11ß-hydroxy-1 6α-methyl-3-oxo- androsta-1, 4-diene-17p-carbothioic acid S-cyanomethyl ester; 6a, 9a-Difluoro-17a- (5-ethyl-isoxazole-3-carbonyl) oxy-11 -hydroxy-16a-methyl-3- oxo-androsta-1, 4-diene-17ß-carboxylic acid cyanomethyl ester; 6a, 9α-Difluoro-11ß-hydroxy-16α-methyl -17α-(5-methylthio-thiophene-2- carbonyl) oxy-3-oxo-androsta-1, 4-diene-17ß-carboxylic acid cyanomethyl ester; 6a, 9a-Difluoro-11 3-hydroxy-17a- (2-isopropyl-1, 3-thiazole-4-carbonyl) oxy-16a- methyl-3-oxo-androsta-1, 4-diene-17ß-carboxylic acid cyanomethyl ester; 17α-(2,2-Dichloro-3,3-dimethylclopropylcarbonyl)oxy-6α,9α -difluoro-11ß-hydroxy- 16a-methyl-3-oxo-androsta-1, 4-diene-17p-carbothioic acid S-cyanomethyl ester; and 17a-(2, 2-Dichloro-3, 3-dimethylclopropylcarbonyl) oxy-6a, 90c-difluoro-11 ß-hydroxy- 16a-methyl-3-oxo-androsta-1, 4-diene-17p-carboxylic acid cyanomethyl ester; especially preferred are 17α-(2,2-Dichloro-3,3-dimethylclopropylcarbonyl)oxy-6α,9α -difluoro-11ß-hydroxy- 16a-methyl-3-oxo-androsta-1, 4-diene-1 (3-carboxylic acid cyanomethyl ester; 6α, 9α-Difluoro-11ß-hydroxy-16α-methyl-3-oxo-17α-(2, 2,3, 3- tetramethyCyclopropylcarbonyl) oxy-androsta-1, 4-diene-17ß-carbothioic acid S-cyanomethyl ester ; and 6α,9α-Difluoro-11ß-hydroxy-16α-methyl-3-oxo-17α-(2,2, 3, 3- tetramethycyclopropylcarbonyl) oxy-androsta-1, 4-diene-1 (3-carboxylic acid cyanomethyl ester Most preferred is 6O, 9α-Difluoro-11ß-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3- tetramethycyclopropylcarbonyl) oxy-androsta-1,4-diene-17ß-carboxylic acid cyanomethyl ester.

The compounds of formula (I) have potentially beneficial anti-inflammatory or anti- allergic effects, particularly upon topical administration, demonstrated by, for example, their ability to bind to the glucocorticoid receptor and to illicit a response via

that receptor. Hence, the compounds of formula (I) are potentially useful in the treatment of inflammatory and/or allergic disorders.

Examples of disease states in which the compounds of the invention may have utility include skin diseases such as eczema, psoriasis, allergic dermatitis neurodermatitis, pruritis and hypersensitivity reactions; inflammatory conditions of the nose, throat or lungs such as asthma (including allergen-induced asthmatic reactions), rhinitis (including hayfever), nasal polyps, chronic obstructive pulmonary disease, interstitial lung disease, and fibrosis; inflammatory bowel conditions such as ulcerative colitis and Crohn's disease; and auto-immune diseases such as rheumatoid arthritis.

Compounds of the invention may also have use in the treatment of conjunctiva and conjunctivitis.

It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established conditions.

As mentioned above, compounds of formula (I) may be useful in human or veterinary medicine, in particular as anti-inflammatory and anti-allergic agents.

There is thus provided as a further aspect of the invention a compound of formula (la or a physiologically acceptable solvate thereof for use in human or veterinary medicine, particularly in the treatment of patients with inflammatory and/or allergic conditions.

According to another aspect of the invention, there is provided the use of a compound of formula (I) or a physiologically acceptable soivate thereof for the manufacture of a medicament for the treatment of patients with inflammatory and/or allergic conditions.

In a further or alternative aspect, there is provided a method for the treatment of a human or animal subject with an inflammatory and/or allergic condition, which method comprises administering to said human or animal subject an effective amount of a compound of formula (I) or physiologically acceptable solvate thereof.

The compounds according to the invention may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions comprising a compound of formula (I) or physiologically acceptable solvate thereof together, if desirable, in admixture with one or more physiologically acceptable diluents or carriers.

Further, there is provided a process for the preparation of such pharmaceutical compositions which comprises mixing the ingredients.

The compounds according to the invention may, for example, be formulated for oral, buccal, sublingual, parenteral, local or rectal administration, especially local administration.

Local administration as used herein, includes administration by insufflation and inhalation. Examples of various types of preparation for local administration include ointments, lotions, creams, gels, foams, preparations for delivery by transdermal patches, powders, sprays, aerosols, capsules or cartridges for use in an inhaler or insufflator or drops (e. g. eye or nose drops), solutions/suspensions for nebulisation, suppositories, pessaries, retention enemas and chewable or suckable tablets or pellets (e. g. for the treatment of aphthous ulcers) or liposome or microencapsulation preparations.

Ointments, creams and gels, may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agent and/or solvents.

Such bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a solvent such as polyethylene glycol. Thickening agents and gelling agents wh ich may be used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, woolfat, beeswax, carboxypoiymethytene and ceiiuiose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifying agents.

Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents.

Powders for external application may be formed with the aid of any suitable powder base, for example, talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilising agents, suspending agents or preservatives.

Spray compositions may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant. Aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain a compound of formula (I) and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, especially 1,1, 1, 2-tetrafluoroethane, 1,1, 1,2, 3,3, 3-heptafluoro-n- propane or a mixture thereof. The aerosol composition may optionally contain additional formulation excipients well known in the art such as surfactants e. g. oleic acid or lecithin and cosolvens e. g. ethanol.

Advantageously, the formulations of the invention may be buffered by the addition of suitable buffering agents.

Capsules and cartridges for use in an inhaler or insufflator, of for example gelatine, may be formulated containing a powder mix for inhalation of a compound of the invention and a suitable powder base such as lactose or starch. Each capsule or cartridge may generally contain between 201lg-10mg of the compound of formula (I).

Alternatively, the compound of the invention may be presented without excipients such as lactose.

The proportion of the active compound of formula (1) in the local compositions according to the invention depends on the precise type of formulation to be prepared but will generally be within the range of from 0. 001 to 10% by weight. Generally, however for most types of preparations advantageously the proportion used will be within the range of from 0.005 to 1% and preferably 0.01 to 0.5%. However, in powders for inhalation or insufflation the proportion used will be within the range of from 0.1 to 5%.

Aerosol formulations are preferably arranged so that each metered dose or"puff"of aerosol contains 201lg-2000llg, preferably about 20pg-500, ug of a compound of

formula (I). Administration may be once daily or several times daily, for example 2, 3,4 or 8 times, giving for example 1,2 or 3 doses each time. The overall daily dose with an aerosol will be within the range 100pg-10mg preferably, 200, ug-2000, ug. The overall daily dose and the metered dose delivered by capsules and cartridges in an inhaler or insufflator will generally be double those with aerosol formulations.

Topical preparations may be administered by one or more applications per day to the affected area; over skin areas occlusive dressings may advantageously be used.

Continuous or prolonged delivery may be achieved by an adhesive reservoir system.

For internal administration the compounds according to the invention may, for example, be formulated in conventional manner for oral, parenteral or rectal administration. Formulations for oral administration include syrups, elixirs, powders, granules, tablets and capsules which typically contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, wetting agents, suspending agents, emulsifying agents, preservatives, buffer salts, flavouring, colouring and/or sweetening agents as appropriate. Dosage unit forms are, however, preferred as described below.

Preferred forms of preparation for internal administration are dosage unit forms i. e. tablets and capsules. Such dosage unit forms contain from 0. 1 mg to 20mg preferably from 2.5 to 10mg of the compounds of the invention.

The compounds according to the invention may in general may be given by internal administration in cases where systemic adreno-cortical therapy is indicated.

In general terms preparations, for internal administration may contain from 0. 05 to 10% of the active ingredient dependent upon the type of preparation involved. The daily dose may vary from 0g1mg to EOmg, @. g. 5-30mg, dependent on the condition being treated, and the duration of treatment desired.

Slow release or enteric coated formulations may be advantageous, particularly for the treatment of inflammatory bowel disorders.

The compound and pharmaceutical formulations according to the invention may be used in combination with or include one or more other therapeutic agents, for

example selected from anti-inflammatory agents, anticholinergic agents (particularly an M1/M2/M3 receptor antagonist), ß2-adrenorecePtor agonists, antiinfective agents (e. g. antibiotics, antivirals), or antihistamines. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutical acceptable salt, solvate or physiologically functional derivative thereof together with one or more other therapeutical active agents, for example selected from an anti-inflammatory agent (for example another corticosteroid or an NSAID), an anticholinergic agent, a ß2-adrenoreceptor agonist, an antiinfective agent (e. g. an antibiotic or an antiviral), or an antihistamine. Preferred are combinations comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a ß2-adrenoreceptor agonist, and/or an anticholinergic, and/or a PDE-4 inhibitor. Preferred combinations are those comprising one or two other therapeutic agents.

It will be clear to a person skilled in the art that, where appropriate, the other therapeutic ingredient (s) may be used in the form of salts, (e. g. as alkali metal or amine salts or as acid addition salts), or prodrugs, or as esters (e. g. lower alkyl esters), or as solvates (e. g. hydrates) to optimise the activity and/or stability and/or physical characteristics (e. g. solubility) of the therapeutic ingredient. It will be clear also that where appropriate, the therapeutic ingredients may be used in optically pure form.

A combination comprising of compound of the invention together with a P2-adrenoreceptor agonist is particularly preferred.

Examples of ß2-adrsnoreceptor agonists include salmeterol (e. g. as racemate or a single enantiomer such as the R-enantiomer), salbutamol, formoterol, salmefamol, fenoterol or terbutaline and salts thereof, for example the xinafoate salt of salmeterol, the sulphate salt or free base of salbutamol or the fumarate salt of formoterol. Long-acting p-adrenoreceptor agonists are preferred, especially those having a therapeutic effect over a 24 hour period such as salmeterol or formoterol.

Preferred long acting ß2-adrenoreceptor agonists include those described in WO 02/066422, WO 02/070490, WO 02/076933, WO 03/024439, WO 03/072539, WO 03/091204, WO 04/016578, WO 2004/022547, WO 2004/037807, WO 2004/037773, WO 2004/037768, WO 2004/039762, WO 2004/039766, W001/42193 and W003/042160.

Especially preferred long-acting p-adrenoreceptor agonists include compounds of formula (XX): or a salt or solvate thereof, wherein: m is an integer of from 2 to 8; n is an integer of from 3 to 11, with the proviso that m + n is 5 to 19, R21 is -XSO2NR26R27 wherein X is -(CH2)p- or C2-6 alkenylene ; R2r and R27 are independently selected from hydrogen, C16alkyl, C3-7cycloalkyl, C (O) NR R, phenyl, and phenyl (C1-4alkyl)-, or R26 and R27, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7-membered nitrogen containing ring, and R26 and R27 are each optionally substituted by one or two groups selected from halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, hydroxy-substituted C1-6 alkoxy, -CO2R28, -SO2NR28R29, -CONR28R29, -NR28C(O)R29, or a 5-, 6-or 7-membered heterocylic ring ; R28 and R29 are independently selected from hydrogen, C1-6alkyl, C3-6cycloalkyl, phenyl, and phenyl (C1-4alkyl)-; and p is an integer of from 0 to 6, preferably from 0 to 4 ; R22 and R23 are independently selected from hydrogen, C1-6alkyl, C1-6alkoxy, halo, phenyl, and C16haloalkyl ; and R24 and R25 are independently selected from hydrogen and C1-4alkyl with the proviso that the total number of carbon atoms in R24 and R25 is not more than 4.

Especially preferred long-acting p2-adrenoreceptor agonists are : 3- (4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl ]ethyl}amino) hexyl] oxy} butyl) benzenesulfonamide ;

3- (3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl] ethyl}- amino) heptyl] oxy} propyl) benzenesulfonamide ; 4- {(1R)-2-[(6-{2-[(2,6-dichlorobenzyl) oxy] ethoxy} hexyl) amino]-1-hydroxyethyl}-2- (hydroxymethyl) phenol ; 4- {(1R)-2-[(6-{4-[3-(cyclopentylsulfonyl)phenyl] butoxy} hexyl) amino]-1-hydroxyethyl}- 2-(hydroxymethyl) phenol ; N- [2-hydroxy-5-[(1R)-1-hydroxy-2-[[2-4-[[(2R)-2-hydroxy-2- phenylethyl] amino] phenyl] ethyl] amino] ethyl] phenyl] foramide, and N-2 {2- [4- (3-phenyl-4-methoxyphenyl) aminophenyl] ethyl)-2-hydroxy-2- (8-hydroxy- 2 (1 H)-quinolinon-5-yl) ethylamine.

Suitable anti-inflammatory agents include corticosteroids. Suitable corticosteroids which may be used in combination with the compounds of the invention are those oral and inhaled corticosteroids and their pro-drugs which have anti-inflammatory activity. Examples include methyl prednisolone, prednisolone, dexamethasone, fluticasone propionate, 6ce, 9α-difluoro-11ß-hydroxy-16α-methyl-17α-[(4-methyl-1, 3- thiazole-5-carbonyl) oxy]-3-oxo-androsta-1, 4-diene-17p-carbothioic acid S- fluoromethyl ester, 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11ß-hydroxy- 16α- <BR> <BR> <BR> methyl-3-oxo-androsta-1, 4-diene-17ß-carbothioic acid S-fluoromethyl ester, 6N, 9N- <BR> <BR> <BR> <BR> difluoro-11 ß-hydroxy-16a-methyl-3-oxo-17c-propionyloxy-androsta-1, 4-diene-17ß- carbothioic acid S-(2-oxo-tetrahydro-furan-3S-yl) ester, beclomethasone esters (eg. the 17-propionate ester or the 17,21-dipropionate ester), budesonide, flunisolide, mometasone esters (eg. the furoate ester), triamcinolone acetone, rofleponide, ciclesonide (16α, 17-[[(R)-cyclohexylmethylene] bis (oxy)]-11ß,21-dihydroxy-pregna- 1, 4-diene-3, 20-dine), butixocort propionate, RPR-106541, and ST-126. Preferred <BR> <BR> <BR> corticosteroids include fluticasone propionate, 6α,9α-difluoro-11ß-hydroxy-16α-<BR> <BR> <BR> <BR> methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-an drosta-1,4-diene-17ß- carbothioic acid Sfluorornethyl ester and 6a, 9α-difluoro-17α-[(2- furanylcarbonyl) oxy]-11ß-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17ß- carbothioic acid S-fluoromethyl ester, more preferably 6a, 9α-difluoro-17α-[(2- furanylcarbonyl) oxy]-11 ß-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17ß- carbothioic acid S-fluoromethyl ester.

Non-steroidal compounds having glucocorticoid agonism that may posess selectivity for transrepression over transactivation and that may be useful in combination therapy include those covered in the following patents: W003/082827, W001/10143,

W098/54159, W004/005229, W004/009016, W004/009017, W004/018429, W003/104195, W003/082787, W003/082280, W003/059899, W003/101932, W002/02565, W001/16128, WOOO/66590, W003/086294, W004/026248, W003/061651, W003/08277.

Suitable anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAID's).

Suitable NSAID's include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (e. g. theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis (eg. montelukast), iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e. g. adenosine 2a agonists), cytokine antagonists (e. g. chemokine antagonists, such as a CCR3 antagonist) or inhibitors of cytokine synthesis, or 5-lipoxygenase inhibitors. Suitable other ß2-adrenoreceptor agonists include salmeterol (e. g. as the xinafoate), salbutamol (e. g. as the sulphate or the free base), formoterol (e. g. as the fumarate), fenoterol or terbutaline and salts thereof. An iNOS (inducible nitric oxide synthase inhibitor) is preferably for oral administration. Suitable INOS inhibitors include those disclosed in W093/13055, W098/30537, W002/50021, W095/34534 and W099/62875. Suitable CCR3 inhibitors include those disclosed in W002/26722.

Of particular interest is use of the compounds of formula (I) in combination with a phosphodiesterase 4 (PDE4) inhibitor, especially in the case of a formulation adapted for inhalation. The PDE4-specific inhibitor useful in this aspect of the invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which are only PDE4. inhibitors, not compounds which inhibit other members of the PDE family, such as PDE3 and PDE5, as well as POTE4.

Compounds of interest include cis-4-cyano-4- (3-cyclopentyloxy-4- methoxyphenyl) cyclohexan-1-carboxylic acid, 2-carbomethoxy-4-cyano-4- (3- cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one and cis- [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenylicyclohexan-1-o l]. Also, cis-4-cyano- <BR> 4.- [3- (cyclopentyloxy)-4-methoxyphenyl] cyclohexane-i-carboxylic acid (also known as cilomilast) and its salts, esters, pro-drugs or physical forms, which is described in

U. S. patent 5,552, 438 issued 03 September, 1996; this patent and the compounds it discloses are incorporated herein in full by reference.

AWD-12-281 from Elbion (Hofgen, N. et al. 15th EFMC Int Symp Med Chem (Sept 6- 10, Edinburgh) 1998, Abst P. 98; CAS reference No. 247584020-9) ; a 9- benzyladenine derivative nominated NCS-613 (INSERM) ; D-4418 from Chiroscience and Schering-Plough ; a benzodiazepine PDE4 inhibitor identified as CI-1018 (PD- 168787) and attributed to Pfizer; a benzodioxole derivative disclosed by Kyowa Hakko in W099/16766 ; K-34 from Kyowa Hakko; V-11294A from Napp (Landells, L. J. et al. Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998] 1998, 12 (Suppl. 28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and a pthalazinone (W099/47505, the disclosure of which is hereby incorporated by reference) from Byk-Gulden ; Pumafentrine, (-)-p- [ (4aR*, 10bS*)-9-ethoxy- 1,2, 3,4, 4a, 1 Ob-hexahydro-8-methoxy-2-methylbenzo [c] [1,6] naphthyridin-6-yl]-N, N- diisopropylbenzamide which is a mixed PDE3/PDE4 inhibitor which has been prepared and published on by Byk-Guiden, now Altana ; arofylline under development by Almirall-Prodesfarma ; VM554/UM565 from Vernais ; or T-440 (Tanabe Seiyaku ; Fuji, K. et al. J Pharmacol Exp Ther, 1998, 284 (1) : 162), and T2585.

Further compounds of interest are disclosed in the published international patent application W004/024728 (Glaxo Group Ltd), PCT/EP2003/014867 (Glaxo Group Ltd) and PCT/EP2004/005494 (Glaxo Group Ltd).

Suitable anticholinergic agents are those compounds that act as antagonists at the muscarinic receptors, in particular those compounds which are antagonists of the Ni or Si3 receptors, dual antagonists of the M1/M3 or M2/M3, receptors or pan- antagonists of the M1/M2/M3 receptors. Exemplary compounds for administration via inhalation include i, oratropium (e. g. as th@ bromide, CAS 22254-24-6, sold under th@ name Atrovent), oxitropium (e. g. as the bromide, CAS 30286-75-0) and tiotropium (e. g. as the bromide, CAS 136310-93-5, sold under the name Spiriva). Also of interest are revatropate (e. g. as the hydrobromide, CAS 262586-79-8) and LAS- 34273 which is disclosed in W001/04118. Exemplary compounds for oral administration include pirenzepine (CAS 28797-61-7), darifenacin (CAS 133099-04- 4, or CAS 133099-07-7 for the hydrobromide sold under the name Enablex), oxybutynin (CAS 5633-20-5, sold under the name Ditropan), terodiline (CAS 15793- 40-5), tolterodine (CAS 124937-51-5, or CAS 124937-52-6 for the tartrate, sold

under the name Detrol), otilonium (e. g. as the bromide, CAS 26095-59-0, sold under the name Spasmomen), trospium chloride (CAS 10405-02-4) and solifenacin (CAS 242478-37-1, or CAS 242478-38-2 for the succinate also known as YM-905 and sold under the name Vesicare).

Other suitable anticholinergic agents include compounds of formula (XXI), which are disclosed in US patent application 60/487981: in which the preferred orientation of the alkyl chain attached to the tropane ring is endo; R3'and R32 are, independently, selected from the group consisting of straight or branched chain lower alkyl groups having preferably from 1 to 6 carbon atoms, cycloalkyl groups having from 5 to 6 carbon atoms, cycloalkyl-alkyl having 6 to 10 carbon atoms, 2-thienyl, 2-pyridyl, phenyl, phenyl substituted with an alkyl group having not in excess of 4 carbon atoms and phenyl substituted with an alkoxy group having not in excess of 4 carbon atoms ; X- represents an anion associated with the positive charge of the N atom. X- may be but is not limited to chloride, bromide, iodide, sulfate, benzene sulfonate, and toluene sulfonate, including, for example : (3-endo)-3-(2,2-di-2-thienylethenyl)-8,8-dimethyl-8-azoniabi cyclo[3.2.1]octane bromide ; (3-endo)-3- (2, 2-dipheny) etheny))-8, 8-dimethy)-8-azoniabicycto [3. 2. 1] octane bromide ; (3-endo)-3- (2, 2-diphenylethenyl)-8, 8-dimethyl-8-azoniabicyclo [3. 2. 1] octane4- methylbenzenesulfonate ; (3-endo)-8, 8-dimethyl-3-[2-phenyl-2-(2-thienyl)ethenyl]-8-azoniabicyclo [3.2. 1] octane bromide; and/or (3-endo)-8, 8-dimethyl-3-[2-phenyl-2-(2-pyridinyl)ethenyl]-8- azoniabicyclo [3.2. 1 octane bromide. Further suitable anticholinergic agents include compounds of formula (XXII) or (XXIII), which are disclosed in US patent application 60/511009:

wherein: the H atom indicated is in the exo position; R4'represents an anion associated with the positive charge of the N atom. R41 may be but is not limited to chloride, bromide, iodide, sulfate, benzene sulfonate and toluene sulfonate ; R42 and R43 are independently selected from the group consisting of straight or branched chain lower alkyl groups (having preferably from 1 to 6 carbon atoms), cycloalkyl groups (having from 5 to 6 carbon atoms), cycloalkyl-alkyl (having 6 to 10 carbon atoms), heterocycloalkyl (having 5 to 6 carbon atoms) and N or O as the heteroatom, heterocycloalkyl-alkyl (having 6 to10 carbon atoms) and N or O as the heteroatom, aryl, optionally substituted aryl, heteroaryl, and optionally substituted heteroaryl ; R44 is slected from the group consisting of (Ci-Ce) alkyl, (C3-C12) cycloalkyl, (C3- C7) heterocycloalkyl, (C1-C6)alkyl(C3-C12)cycloalkyl, (C1-C6)alkyl(C3- C7) heterocycloalkyl, aryl, heteroaryl, (Ci-Ce) alkyl-aryl, (C1-C6)alkyl-heteroaryl, -OR45, -CH2OR45, -CH2OH, -CN, -CF3, -CH2O (CO)R46, -CO2R47, -CH2NH2, - CH2N (R47)SO2R45, -SO2N(R47)(R48), -CON(R47)(R48), -CH2N(R48)CO(R46), - CH (48) SO2(R46), -CH2N(R48)CO2(R45), -CH2N(R48)CONH(R47); R45 is selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkyl(C3- C12) cycloalkyl, (C1-C6)alkyl(C3-C6)heterocycloalkyl, (C1-C6)alkyl-aryl, (C1-C6)alkyl- heteroaryl ; R46 is selected from the group consisting of (Ci-Ce) alkyl, (C3-C12) cycloalkyl, (C3- C7) heterocycloalkyl, (C1-C6)alkyl(C3-C12)cycloalkyl, (C1-C6)alkyl(C3- C7) heterocycloalkyl, aryl, heteroaryl, (C1-C6) alkyl-aryl, (C1-C6) alkyl-heteroaryl ; R47 and R48 are, independently, selected from the group consisting of H, (Ci-Ce) alkyl, (C3-C12)cycloalkyl, (C3-C7)heterocycloalkyl, (C1-C6)alkyl(C3-C12)cycloalkyl, (C1-

C6) alkyl(C3-C7)heterocycloalkyl, (C1-C6)alkyl-aryl, and (Ci-Ce) alkyl-heteroaryl, including, for example: (Endo)-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl -8-azonia- bicyclo [3.2. 1] octane iodide; 3-((Endo)-8-methyl-8-aza-bicyclo [3.2. 1] oct-3-yl)-2, 2-diphenyl-propionitrile ; (Endo)-8-methyl-3-(2, 2, 2-triphenyl-ethyl)-8-aza-bicyclo [3.2. 1] octane; 3-((Endo)-8-methyl-8-aza-bicyclo [3.2. 1] oct-3-yl)-2, 2-diphenyl-propionamide ; 3-((Endo)-8-methyl-8-aza-bicyclo [3.2. 1] oct-3-yl)-2, 2-diphenyl-propionic acid ; (Endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia- bicyclo [3.2. 1] octane iodide; (Endo)-3-(2-cyano-2, 2-diphenyl-ethyl)-8, 8-dimethyl-8-azonia-bicyclo [3.2. 1] octane bromide; 3-((Endo)-8-methyl-8-aza-bicyclo [3.2. 1] oct-3-yl)-2, 2-diphenyl-propan-1-ol ; N-Benzyl-3-((endo)-8-methyl-8-aza-bicyclo [3.2. 1] oct-3-yl)-2, 2-diphenyl- propionamide; (Endo)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azo nia- bicyclo [3.2. 1] octane iodide; 1-Benzyl-3-[3-((endo)-8-methyl-8-aza-bicyclo[3. 2.1] oct-3-yl)-2, 2-diphenyl-propyl]- urea ; 1-Ethyl-3-[3-((endo)-8-methyl-8-aza-bicyclo [3.2. 1] oct-3-yl)-2, 2-diphenyl-propyl]-urea ; N-[3-((Endo)-8-methyl-8-aza-bicyclo [3. 2. 1] oct-3-yl)-2, 2-diphenyl-propyl]-acetamide ; N- [3- ( (Endo)-8-methyl-8-aza-bicyclo [3.2. 1] oct-3-yl)-2, 2-diphenyl-propyl]-benzamide ; 3-((Endo)-8-methyl-8-aza-bicyclo [3.2. 1] oct-3-yl)-2, 2-di-thiophen-2-yl-propionitrile ; (Endo)-3-(2-cyano-2, 2-di-thiophen-2-yl-ethyl)-8, 8-dimethyl-8-azonia- bicyclo [3. 2. 1] octane iodide ; N- 3- ( (Endo)-8-methyl-8-aza-bicyclo [3. 2. 1] oct-3-yl)-2, 2-diphenyl-propyl]- benzenesulfonamide ; [3- ( (Endo)-8-methyl-8-aza-bicyclo [3. 2. 1] oct-3-yl)-2, 2-diphenyl-propyl]-urea ; N- [3-((Endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphen yl-propyl]- methanesulfonamide ; and/or (Endo)-3- {2, 2-diphenyl-3-[(1-phenyl-methanoyl)-amino]-propyl}-8,8-dimeth yl-8- azonia-bicyclo [3.2. 1] octane bromide.

More preferred compounds useful in the present invention include : (Endo)-3- (2-methoxy-2, 2-di-thiophen-2-yl-ethyl)-8, 8-dimethyl-8-azonia- bicyclo [3. 2. 1]ocatane iodide;

(Endo)-3-(2-cyano-2, 2-diphenyl-ethyl)-8, 8-dimethyl-8-azonia-bicyclo [3.2. 1] octane iodide; (Endo)-3-(2-cyano-2, 2-diphenyl-ethyl)-8, 8-dimethyl-8-azonia-bicyclo [3. 2. 1] octane bromide; (Endo)-3- (2-carbamoyl-2, 2-diphenyl-ethyl)-8, 8-dimethyl-8-azonia- bicyclo [3.2. 1] octane iodide; (Endo)-3- (2-cyano-2, 2-di-thiophen-2-yl-ethyl)-8, 8-dimethyl-8-azonia- bicyclo [3.2. 1] octane iodide; and/or (Endo)-3-{2, 2-diphenyl-3-[(1-phenyl-methanoyl)-amino]-propyl}-8, 8-dimethyl-8- azonia-bicyclo [3.2. 1] octane bromide.

Suitable antihistamines (also referred to as H1-receptor antagonists) include any one or more of the numerous antagonists known which inhibit H1-receptors, and are safe for human use. First generation antagonists, include derivatives of ethanolamines, ethylenediamines, and alkylamines, e. g diphenylhydramine, pyrilamine, clemastine, chloropheniramine. Second generation antagonists, which are non-sedating, include loratidine, desloratidine, terfenadine, astemizole, acrivastine, azelastine, levocetirizine fexofenadine and cetirizine.

Examples of preferred anti-histamines include loratidine, desioratidine, fexofenadine and cetirizine.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor.

The invention thus provides, in a further aspect, a combination comprising compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a ß2-adrenorecptor agonist.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutical acceptable salt, solvate or physiologically functional derivative thereof together with an antihistamine.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor and a ß2- adrenoreceptor agonist.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic and a PDE-4 inhibitor.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutical acceptable diluent or carrier represent a further aspect of the invention.

The individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.

Preferably the individual compounds of such combinations may be administered simultaneously in a combined pharmaceutical combination. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.

The compounds of formula (I) and solvates thereof may be prepared by the methodology described hereinafter, constituting a further aspect of this invention.

The compounds of formula (1) and solvates thereof may be prepared by the methodology described hereinafter, constituting a further aspect of this invention.

A process according to the invention for preparing a compound of formula (I) comprises reaction of a carboxylic acid (X=O) or carbothioic acid (X=S) of formula (lI)

wherein Ri, R2, R3, R4, X and # are as defined above, with a compound of formula L-CH2-CN wherein L represents a leaving group.

In this process the compound of formula (II) may be reacted with a compound of formula L-CH2-CN wherein L represents a leaving group such as halogen atom or a tosyl or mesyl group or the like, under standard conditions. For example the reaction may be performed in an inert polar organic solvent e. g. N, N-dimethylformamide in the presence of a base e. g. potassium carbonate, sodium bicarbonate.

Compounds of formula (II) may conveniently be employed as salts when such salts may be prepared in crystalline form, or as solvates.

Compounds of formula L-CH2-CN are either known or may be prepared by known methods.

Compounds of formula (II) may be prepared from the corresponding 17a-hydroxyl derivative of formula (Ill) : wherein R2, R3, R4, X and # are as defined above,

using for example, the methodology described by G. H. Phillipps et al., Journal of Medicinal Chemistry, (1994), 37,3717-3729. The step typically comprises the addition of a reagent suitable for performing the esterification to the ester such as a compound of formula R1COOH or an activated derivative thereof eg an activated ester, anhydride or halide thereof especially an acid halide eg the acid chloride in the presence of a mild base e. g. triethylamine. Imidazolium esters may offer convenient alternatives to the acid chloride in this reaction. For example the 1,2- dimethyl-1 H-imidazolium ester (IV) represents a convenient crystalline activated derivative of 2,2, 3, 3-tetramethylcyclopropane carboxylic acid.

Generally the acid chloride or other activated carboxylic acid derivative would be employed in at least 2 times molar quantity relative to the compound of formula (III).

The second mole of acid chloride tends to react with the carboxylic/carbothioc acid moiety in the compound of formula (111) and would need to be removed by reaction with an amine such as diethylamine or 1-methylpiperazine.

In a further aspect of the invention there is provided a process for preparing a compound of formula (H)

where Ri represents 2, 2, 3, 3-tetramethyl cyclopropyl and R2, Rs, R4, X and # are defined above, which process comprises reaction of the 1, 2-dimethyl-1 H- imidazolium ester of 2,2, 3, 3-tetramethylcyclopropane carboxylic acid (IV) : with the corresponding 17a-hydroxyl derivative of formula (III)

Compounds of formula (III) are either known or may be prepared in accordance with procedures described by G. H. Phillipps et al., Journal of Medicinal Chemistry, (1994), 37,3717-3729.

The following compounds of formula (11) are new and form an aspect of the invention: 17a-(4-[(Diethylamino) sulphonyl] benzoyl) oxy-6a, 9a-difluoro-11 ß-hydroxy-16a- methyl-3-oxo-androsta-1, 4-diene-17p-carbothioic acid, 6a, 9a-Difluoro-17a-(2, 6-difluorobenzoyl) oxy-11 ß-hydroxy-16a-methyl-3-oxo- androsta-1, 4-diene-17ß-carboxylic acid, <BR> <BR> <BR> <BR> 6a, 9α-Difluoro-1 1ß-hydroxy-17α-(4-methoxybenzoyl)oxy-16α-methyl-3-oxo-< ;BR> <BR> <BR> <BR> <BR> <BR> androsta-1, 4-diene-17p-carboxylic acid, <BR> <BR> <BR> <BR> <BR> <BR> 17α-(4-Cyanobenzoyl)oxy-6α,9α-difluoro-11ß-hydroxy-16α- methyl-3-oxo-androsta- 1, 4-diene-17ß-carboxylic acid, 6a, 9α-Difluoro-17α-(3,3-dimethylbutanoyl)oxy-11ß-hydroxy-16 -methyl-3-oxo- androsta-1, 4-diene-17ß-carboxylic acid, 6α,9α-Difluoro-11ß-hydroxy-17α-(2-isopropyl-1,3-thiazole -4-carbonyl)oxy-16α- methyl-3-oxo-androsta-1, 4-diene-17p-carboxylic acid, 6a, 9α-Difluoro-11ß-hydroxy-16α-methyl-3-oxo-17α-(quinoline- 2-carbonyl) oxy- androsta-1, 4-diene-17p-carboxylic acid, 6a, 9α-Difluoro-11ß-hydroxy-16α-methyl-3-oxo-17α-(5-trifluor omethyl-furan-2- carbonyl) oxy-androsta-1, 4-diene-17ß-carboxylic acid,

6a, 9a-Difluoro-11 i-hydroxy-16a-methyl-17a- (5-methylsulphonyl-thiophene-2- carbonyl) oxy-3-oxo-androsta-1, 4-diene-17ß-carboxylic acid, 6a, 9α-Difluoro-11ß-hydroxy-16α-methyl-17α-(5-methylthio-thi ophene-2- carbonyl) oxy-3-oxo-androsta-1, 4-diene-17p-carboxylic acid, 6a, 9α-Difluoro-17α-(5-ethyl-isoxazole-3-carbonyl)oxy-11ß-hyd roxy-16α-methyl-3- oxo-androsta-1, 4-diene-17p-carboxylic acid, <BR> <BR> <BR> 17α-(5-Chloro-4-methoxy-thiophene-3-carbonyl)oxy-6α,9α-di fluoro-11ß-hydroxy-16α- methyl-3-oxo-androsta-1, 4-diene-17ß-carboxylic acid, 17a-(2, 2-Dichloro-3, 3-dimethylclopropylcarbonyl) oxy-6a, 9a-difluoro-11 ß-hydroxy- 16a-methyl-3-oxo-androsta-1, 4-diene-17ß-carboxylic acid, 17a- (2, 2-Dichloro-3, 3-dimethylclopropylcarbonyl) oxy-6a, 9a-difluoro-11 (3-hydroxy- 16a-methyl-3-oxo-androsta-1, 4-diene-17ß-carbothioic acid, 6a, 9a-Difluoro-11 3-hydroxy-16a-methyl-17a- (5-methylsulphonyl-thiophene-2- carbonyl) oxy-3-oxo-androsta-1, 4-diene-17ß-carbothioic acid, 6a, 9a-Difluoro-11 ß-hydroxy-16α-methyl-3-oxo-17α-(5-trifluoromethyl-furan-2 - carbonyl) oxy-androsta-1, 4-diene-17ß-carbothioic acid, and <BR> <BR> <BR> 6α,9α-Difluoro-17α-(3-(difluoromethylthio)benzoyl)oxy-11 -hydroxy-16α-methyl-3-<BR> <BR> <BR> <BR> oxo-androsta-1, 4-diene-17ß-carbothioic acid.

Compound of formula (IV),3-dimethyl-1-[(2, 2,3, 3-tetramethylcyclopropyl) carbonyl]- 1 H-imidazol-3-ium chloride is new and forms an aspect of the invention.

Compounds of formula (III) may also be prepared by a process comprising the following steps : 0 " N CH, OH CHO, CH, F o F Step (a) comprises oxidation of a solution containing the compound of formula (V) to give the carboxylic acid (III, X = O) ;

Preferably, step (a) will be performed in the presence of a solvent comprising methanol, water, tetrahydrofuran, dioxan or diethylene glygol dimethylether. For example, so as to enhance yield and throughput, preferred solvents are methanol, water or tetrahydrofuran, and more preferably are water or tetrahydrofuran, especially water and tetrahydrofuran as solvent. Dioxan and diethylene glygol dimethylether are also preferred solvents which may optionally (and preferably) be employed together with water. Preferably, the solvent will be present in an amount of between 3 and 10vol relative to the amount of the starting material (1wt.), more preferably between 4 and 6 vol., especially 5 vol. Preferably the oxidising agent is present in an amount of 1-9 molar equivalents relative to the amount of the starting material. For example, when a 50% w/w aqueous solution of periodic acid is employed, the oxidising agent may be present in an amount of between 1.1 and 10wt. relative to the amount of the starting material (1wt.), more preferably between 1.1 and 3wt., especially 1.3wt. Preferably, the oxidation step will comprise the use of a chemical oxidising agent. More preferably, the oxidising agent will be periodic acid or iodic acid or a salt thereof. Most preferably, the oxidising agent will be periodic acid or sodium periodate, especially periodic acid. Alternatively (or in addition), it will also be appreciated that the oxidation step may comprise any suitable oxidation reaction, eg. one which utilises air and/or oxygen. When the oxidation reaction utilises air and/or oxygen, the solvent used in said reaction will preferably be methanol. Preferably, step (a) will involve incubating the reagents at room temperature or a little warmer, say around 25 °C eg for 2 hours. The compound of formula (III, X=O) may be isolated by recrystallisation from the reaction mixture by addition of an anti-solvent. A suitable anti-solvent for compound of formula (III, X=O) is water. Surprisingly we have discovered that it is highly desirable to control the cona'itions under which the compound of formula gill, X is precipitated by addition of anti-solvent eg water. When the recrystallisation is performed using chilled water (eg water/ice mixture at a temperature of 0-5 OC) although better anti- <BR> <BR> <BR> solvent properties may be expected we ha e found that the crystalline product produced is very voluminous, resembles a soft gel and is very difficult to filter.

Without being limited by theory we believe that this low density product contains a large amount of solvate solvent within the crystal lattice By contrast when conditions of around 10 °C or higher are used (eg around ambient temperature) a granular product of a sand like consistency which is very easily filtered is produced.

Under these conditions, crystallisation typically commences after around 1 hour and is typically completed within a few hours (eg 2 hours). Without being limited by

theory we believe that this granular product contains little or no of solvated solvent within the crystal lattice.

Step (b) will typically comprise the addition of a reagent suitable for converting the carboxylic acid (III, X = O) into the carbothioic acid (III, X = S) eg. using hydrogen sulphide gas together with a suitable coupling agent eg. carbonyidiimidazole (CDI) in the presence of a suitable solvent eg. dimethylformamide.

Solvates of compounds of formula (I) which are not physiologically acceptable may be useful as intermediates in the preparation of compounds of formula (I) or physiologically acceptable solvates thereof.

Compounds of formula (I) and/or salts or solvates thereof demonstrate agonism at the glucocorticoid receptor.

Compounds of formula (I) and/or salts or solvates thereof may demonstrate good anti-inflammatory properties, with predictable pharmacokinetic and pharmacodynamic behaviour. They also may have an attractive side-effect profile, demonstrated, for example, by increased selectivity for the glucocorticoid receptor over the progesterone receptor and/or increased selectivity for glucocorticoid receptor mediated transrepression over transactivation and are likely to becompatible with a convenient regime of treatment in human patients.

The following non-limiting Examples illustrate the invention: <BR> <BR> <BR> <BR> <BR> <BR> <BR> EXAMPLES<BR> General Chromatographic purification was performed using pre-packed Bond Elut silica gel cartridges available commercially from Varian or by flash chromatography on pre- packed Biotage silica columns. These cartridges were pre-conditioned with dichloromethane prior to use. LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm x 4. 6 mm ID) eluting with 0. 1% HCO2H and 0.01 M ammonium acetate in water (solvent A), and 0.05% HC02H 5% water in acetonitrile (solvent B), using the following elution gradient 0-0.7 min 0% B, 0.7-4. 2 min 100% B, 4.2-5. 3 min 0% B, 5.3-5. 5 min 0% B at a flow rate of 3 ml/min. The mass spectra were recorded on a Fisons VG Platform spectrometer using electrospray positive and negative mode (ES+ve and ES-ve).'H NMR spectra were obtained in CDCI3 on a Bruker DPX

400 spectrometer working at 400.13 MHz and 9.4 Tesla using as internal standard the signal from the residual protonated solvent at 7.25 ppm.

Intermediates Intermediate 1: 6α, 9a-Difluoro-1113-hvdroxv-16a-methvl-3-oxo-17a- (2, 2, 3, 3- tetramethvcvclopropvlcarbonvl) oxy-androsta-1, 4-diene-17ß-carbothioic acid Oxalyl chloride (3ml, 34. 9mmol) was added to a stirred and cooled (ice) solution of 2,2, 3, 3-tetramethylcyclopropyl carboxylic acid (2.48g, 17. 45mmol) in dry dichloromethane (70ml) containing diethylformamide (2drops) and the mixture stirred for 3h. The solvent was evaporated and residual acid chloride was redissolved in dichloromethane (15ml) and added to a stirred and cooled (ice) solution of 6a, 9a- difluoro-11 i, 17a,-dihydroxy-16a-methyl-3-oxo-androsta-1, 4-diene-17p-carbothioic acid (G. H. Phillipps et al., (1994) Journal of Medicinal Chemistry, 37,3717-3729) (3g, 7. 27mmol) in dichloromethane (120ml) containing triethylamine (2. 03ml, 14. 5mmol). The mixture was allowed to warm to room temperature and after 1.5h was washed successively with aqueous sodium bicarbonate (150ml), 1 M hydrochloric acid (150mi) and brine (150mi) and dried through a hydrophobic frit and evaporated. The residual solid was dissolved in dioxane (140ml) and 1- methylpiperazine (3. 23mi, 29. 1mmol) was added and the mixture stirred for 4h. The mixture was then added slowly to a vigorously stirred mixture of 2M hydrochloric acid (200ml) and ice (200moi). The mixture was extracted with dichloromethane (300ml) and the extract washed with water and dried through a hydrophobic frit and evaporated. This material was dissolved in dioxane (80ml) and treated again with 1- methylpiperazine (3. 23mi) for 20h. The mixture was added slowly to a vigorously stirred mixture of 2M hydrochloric acid (200moi) and ice (200ml). The mixture was <BR> <BR> <BR> extracted with dichloromethane (30Oml) and the extract washed with water and dried through a hydrophobic frit and evaporated. Purification by chromatography on a 90g biotage cartridge using initially cyclohexane and finally cyclohexane : ethyl acetate (3 : 1) ) yielded the title compound (1.33g) : LCMS retention time 3. 99 min.

Intermediate 2: 17α-(4-[(Diethylamino)sulphonyl]benzoyl)oxy-6α,9α-difluor o-11ß- hydroxy-16 (x-methvl-3-oxo-androsta-1. 4-diene-1773-carbothioic acid 4-[(Diethylamino) sulphonyl] benzoyl chloride (134mg) was added to a stirred solution of 6α,9α-difluoro-11ß,17α-dihydroxy-16α-methyl-3-oxo-andro sta-1,4-diene-17ß- carbothioic acid (200mg) in pyridine (8ml) and the mixture stirred under nitrogen for 2h. More acid chloride (134mg) was the mixture stirred for a further 2h. 6M HCI

(60moi) was then added and the mixture extracted with ethyl acetate (3x30ml). The combined organic extracts were washed with 2M HCI (30moi), dried through a hydrophobic frit and evaporated to give the title compound as a white foam : LCMS retention time 4.26 min.

Intermediate 3: 17α-(5-Chloro-4-methoxy-thiophene-3-carbonyl)oxy-6α,9α-di fluoro- 11ß-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17ß-carbo thioic acid Prepared using methods similar to that described for Intermediate 2. LCMS retention time 4.06 min.

Intermediate 4: 6cc, 9α-Difluoro-11ß-hydroxy-16α=methyl-3-oxo-17α-(2,2,3, 3- tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17ß-ca rboxylic acid Prepared from 6a, 9α-difluoro-11ß,17α-dihydroxy-16α-methyl-3-oxo-androsta- 1, 4- diene-17ß-carboxylic acid (G. H. Phillipps et al., (1994) Journal of Medicinal Chemistry, 37,3717-3729) using methods similar to that described for Intermediate 1. LCMS retention time 3.59 min.

Intermediate 5: 17α-(Cyclohexylcarbonyl)oxy-6α,9α-difluoro-11ß-hydroxy-1 6α- methyl-3-oxo-androsta-1, 4-diene-17ß-carboxylic acid Cyclohexanecarbonyl chloride (0. 081 ml, 0. 6mmol) was added to a stirred and cooled (ice) solution of 6α,9α-difluoro-11ß,17α-dihydroxy-16α-methyl-3-oxo-andro sta-1,4- diene-17p-carboxylic acid (200mg, 0. 5mmol) in pyridine (3ml) and the mixture stirred for 2h and then poured into 2M HCI. The mixture was extracted twice with ethyl acetate and the combined organic extracts were washed successively with 2M HCI and brine and evaporated to give the title compound (296mg) : LCMS retention time 3. 67 min. intermediate 6: 6α,9α-Difluoro-17α-(2,6-difluorobenzoyl)oxy-11ß-hydroxy- 16α- methyl-3-oxo-androsta-1,4-diene-17ß-carboxylic acid Prepared using methods similar to that described for Intermediate 5. LCMS retention time 3.45 min.

Intermediate 7: 6α, 9α-Difluoro-11ß-hydroxy-17α-(4-methoxybenzoyl)oxy-16α-me thyl- 3-oxo-androsta-1, 4-diene-17ß-carboxylic acid Prepared using methods similar to that described for Intermediate 5. LCMS retention time 3.38 min.

Intermediate 8: 17α-(4-Cyanobenzoyl)oxy-6α,9α-difluoro-11ß-hydroxy-16α- methyl-3- oxo-androsta-1, 4-diene-17i-carboxylic acid Prepared using methods similar to that described for Intermediate 5. LCMS retention time 3.36 min.

Intermediate 9: 17a- (Cyclopentylmethvlcarbonvl) oxv-6a. 9a-difluoro-11 .-hvdroxy- 16a-methyl-3-oxo-androsta-1, 4-diene-17ß-carboxYlic acid Prepared using methods similar to that described for Intermediate 5. LCMS retention time 3.65 min.

Intermediate 10: 6,. 9a-Difluoro-17a- (3, 3-dimethylbutanovl) oxv-11 3-hydroxy-16a- methyl-3-oxo-androsta-1, 4-diene-17ß-carboxelic acid Prepared using methods similar to that described for Intermediate 5. LCMS retention time 3.46 min.

Intermediate 11: 6α,9α-Difluoro-11ß-hydroxy-17α-(2-isopropyl-1,3-thiazole -4- carbonyl)oxy-16α-methyl-3-oxo-androsta-1,4-diene-17ß-carbo xylic acid Prepared using methods similar to that described for Intermediate 5. LCMS retention time 3. 38 min.

Intermediate 12: 6a, 9α-Difluoro-11ß-hydroxy-16α-methyl-3-oxo-17α-(quinoline- 2- carbonyl) oxy-androsta-1,4-diene-17ß-carboxylic acid Prepared using methods similar to that described for Intermediate 5. LCMS retention time 3.46 min.

Intermediate 13: 6α,9α-Difluoro-11ß-hydroxy-16αmethyl-3-oxo-17α-(5- trifluoromethyl-furan-2-carbonyl) oxy-androsta-1,4-diene-17ß-carboxylic acid Prepared using methods similar to that described for Intermediate 5. LCMS retention time 3. 61 min.

Intermediate 14: 6α,9α-Difluoro-11ß-hydroxy-16α-methyl-17α-(5-methylsulp honyl- thiophene-2-carbonvl) oxy-3-oxo-androsta-1, 4-diene-1 70-carboxylic acid Prepared using methods similar to that described for Intermediate 5. LCMS retention time 3. 28 min.

Intermediate 15: 6α,9α-Difluoro-11ß-hydroxy-16α-methyl-17α-(5-methylthio - thiophene-2-carbonyl) oxy-3-oxo-androsta-1, 4-diene-17ß-carboxylic acid Prepared using methods similar to that described for Intermediate 5. LCMS retention time 3.69 min.

Intermediate 16: 6a, 9a-Difluoro-17a- (5-ethvl-isoxazole-3-carbonvl) oxv-11f3-hvdroxy- 16a-methyl-3-oxo-androsta-1, 4-diene-17ß-carboxylic acid Prepared using methods similar to that described for Intermediate 5. LCMS retention time 3.45 min.

Intermediate 17: 9a-Fluoro-11 3-hydroxv-16 Q-methvl-3-oxo-17a- (2, 2. 3, 3- tetramethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17ß-c arboxylic acid Prepared from 11ß,17α-dihydroxy-9α-fluoro-16ß-methyl-3-oxo-androsta-1, 4-diene- 17ß-carboxylic acid (G. H. Phillipps et al., (1994) Journal of Medicinal Chemistry, 37, 3717-3729) and 2,2, 3, 3-tetramethylcyclopropyl carbonyl chloride using methods similar to that described for Intermediate 5. LCMS retention time 3.75 min.

Intermediate 18 : 17α-(5-Chloro-4-methoxy-thiophene-3-carbonyl)oxy-6α,9α-di fluoro- 14ß-hydroxy-16α-methyl -3-oxo-androsta-1,4-diene-17ß-carboxylic acid Prepared using methods similar to that described for Intermediate 5. LCMS retention time 3.59 min.

Intermediate 19 : 17α-(2,2-Dichloro-3,3-dimethylclopropylcarbonyl)oxy-6α,9α -difluoro- 11ß-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17ß-carbo xylic acid Prepared using methods similar to that described for Intermediate 1. LCMS retention time 3. 58 min.

Intermediate 20 : 17α-(2,2-Dichloro-3,3-dimethylclopropylcarbonyl)oxy-6α,9α -difluoro- 11ß-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17ß-carbo thioic acid

Prepared using methods similar to that described for Intermediate 1. LCMS retention time 4.10, 4.19 min.

Intermediate 21: 17α- (Cyclohexvlcarbonvl) oxv-6a.,9a-difluoro-11 a-hydrox-y116a- methvl-3-oxo-androsta-1, 4-diene-17ß-carbothioic acid Prepared using methods similar to that described for Intermediate 1. LCMS retention time 4. 17min.

Intermediate 22: 6a, 9α-Difluoro-11ß-hydroxyu-16α-methyl -17α-(5-methylsulphonyl- thiophene-2-carbonyl) oxy-3-oxo-androsta-1,4-diene-17ß-carbothioic acid Prepared using methods similar to that described for Intermediate 1. LCMS retention time 4.10 min.

Intermediate 23: 6α,9α-Difluoro-11ß-hydroxy-16α-methyl-3-oxo-17α-(5- trifluoromethyl-furan-2-carbonyl)oxy-androsta-1,4-diene-17ß -carbothioic acid Prepared using methods similar to that described for Intermediate 1. LCMS retention time 4.45 min.

Intermediate 24 : 6α, 9α-Difluoro-17α- (3-(difluoromethylthio)benzoyl)oxy-11ß-hydroxy- 16α-methyl-3-oxo-androsta-1,4-diene-17ß-carbothioic acid Prepared using methods similar to that described for Intermediate 1. LCMS retention time 4. 23 min.

Intermedial 25 e 25: 2,3-dimethyl-1-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H - imidazol-3-ium chloride Oxalyl chloride (360ml, 41mol) 1 mol) was added over 65min to a stirred solution of 2, 2, 3, 3-tetramethylcyclopropane carboxylic acid (600g, 4. 2mol) in dichloromethane (3.6L) at 34°C. The solution was then heated to reflux for 30 min and then cooled to 5°C. A solution of 1, 2-dimethylimidazole (490g, 5. 1mol) in dichloromethane (1.2L) was added over 45min maintaining the internal temperature around 5°C. The resulting suspension was then warmed to 18°C and acetone (4. 8L) was added over 45 minutes maintaining the internal temperature around 18°C. The slurry was cooled to 5°C over 30 minutes, stirred at 5°C for 30 minutes and then filtered. The product

was colected by filtration, washed with acetone: dichloromethane (3: 1, 3x1. 2L), sucked dry and then dried in a vacuum oven at 25-30°C for 10 hours to give Intermediate 25 as a white solid (890g) 1H nmr: 8n (CDCI3, 400MHz) 8. 45 (d, J 2.4Hz, 1H), 8.11 (d, J 2.4Hz, 1H), 4.21 (s, 3H), 2.96 (s, 3H), 2.21 (s, 1H), 1.43 (s, 6H), 1.33 (s, 6H).

Examples Example 1: 6α, 9α-Difluoro-11ß-hydroxy-16α-methyl-3-oxo-17α-(2,2,3, 3- tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17ß-ca rbothioic acid S- cyanomethyl ester Bromoacetonitrile (0. 042ml, 0. 6mmol) was added to a stirred and cooled (ice) solution of Intermediate 1 (120mg, 0. 22mmol) and sodium hydrogen carbonate (21mg, 0. 245mmol) in DMF (3ml) under nitrogen and the mixture stirred at room temperature for 18h. Diethylamine (0. 03ml, 0. 29mmol) was added and the mixture stirred for 15min when 2M HCI (4ml) and then water (5ml) and dichloromethane (5ml) were added. The organic phase was separated washed successively with aqueous sodium hydrogen carbonate (5ml) and brine (5ml) and dried through a hydrophobic frit and evaporated to dryness. Purification on a Bon Elut cartridge using initially cyclohexane and finally cyclohexane : ethyl acetate 3 : 1 gave the title compound (86mg) : LCMS retention time 3. 82 min, m/z 576 MH+ Example 2: 17α-(4-[(Diethylamino)sulphonyl]benzoyl)oxy-6α,9α-difluor o-11ß- <BR> <BR> <BR> hYdroxy-16a-methyl-3-oxo-androsta-114-diene-17ß-carbothioic acid S-cyanomethyl ester Example 2 was prepared from Intermediate 2 using a method similar to that described for Example 1. LCMS retentio time 3.62 min, m/z 691 MH+ Example 3: 17α-(5-Chloro-4-methoxy-thiophene-3-carbonyl)oxy-6α,9α-di fluoro-11ß- <BR> <BR> <BR> hydroxy-16α-methyl -3-oxo-androsta-1,4-diene-17ß-carbothioic acid S-cyanomethyl ester Example 3 was prepared from Intermediate 3 using a method similar to that described for Example 1. LCMS retention time 3. 58 min, m/z 626/628 MH+ Example 4 : 6α, 90C-Difluoro-11 ß-hvdroxy-16a-methvl-3-oxo-170c-(2, 2, 3, 3- tetramethycyclopropylcarbonyl) oxy-androsta-1,4-diene-17ß-carboxylic acid cyanomethyl ester

Method A Bromoacetonitrile (0. 229ml, 3. 29mmol) was added to a stirred and cooled (ice) solution of Intermediate 4 (634mg, 1. 22mmol) and sodium carbonate (1.29g, 12. 2mmol) in DMF (15ml) under nitrogen and the mixture stiirred at room temperature for 2h. More sodium carbonate (258mg) was added and the mixture stirred for a further 18h. 2M HCI (20moi) was added dropwise follwed by water (25moi) and the mixture was extracted with ethyl acetate (2x50ml). The combined organic extracts were washed successively with aqueous sodium hydrogen carbonate (50moi) and brine (50moi) and dried through a hydrophobic frit and evaporated to dryness.

Purification on a Bon Elut cartridge using initially cyclohexane and finally cyclohexane : ethyl acetate 3: 1 gave the title compound as a white solid (485mg): LCMS retention time 3.79 min, m/z 560 MH+ Method B 6α,9α-Difluoro-11ß,17α-dihydroxy-16α-methyl-3-oxo-andro sta-1,4-diene-17ß- carboxylic acid (490g, 1. 2mol) and Intermediate 25 (790g, 3. 1mol) were suspended in 3-pentanone (7. 3L). To the stirred suspension was added over 10 min a solution of 1, 2-dimethylimidazole (120g, 1. 2mol) in water (730ml) maintaining the internal temperature around 19°C. After 35 min, 1-methylpiperazine (230ml, 2. 1mol) was added over 10 min keeping the internal temperature around 19°C. The mixture was stirred for 30 min and then washed sequentially with 2M HCI (290ml) and water (290ml). Diisopropylethylamine (430ml, 2. 5mol) and bromoacetonitrile (120ml, 1. 7mol) were added sequentially to the solution and the mixture was heated to 53°C for 13 hours. The solution was cooled to 341°C and 1-methylpiperazine (105ml) was added. The mixture was stirred around 34°C for a further hour, cooled to 25°C and washed sequentially with 2M HCI (2dom), water (290ml), 2% potassium carbonate solution (290ml) and water (290m)). The organic solution was concentrated to 3. 9L by atmospheric distillation, cooled to 75°C and seeded with crystals of Example 4.

2, 2, 4-Trimethylpentane (6. 83L) was added over 3 hours at 75°C and the slurry was then cooled to 10°C over 2 hours, stirred for a further 30min and then filtered. The product was washed with 3-pentanone: 2,2, 4-trimethylpentane (1: 3, 3x1L), sucked dry and finaly dried in a vacuum oven at 50°C for 12 hours to give Example 4 as a white solid (640g) identical to material olbtained using Method A.

Example 5: 17a- (Cyclohexylcarbonvl) oxv-6a, a-difluoro-11 3-hvdroxv-16a-methvl-3- oxo-androsta-1, 4-diene-17ß-carboxylic acid cyanomethyl ester Example 5 was prepared from Intermediate 5 using a method similar to that described for Example 4. LCMS retention time 3.65 min, m/z 546 MH+ Example 6: 6α,9α-Difluoro-17α-(2,6-difluorobenzoyl)oxy-11ß-hydroxy- 16α-methyl-3- oxo-androsta-1, 4-diene-1 (3-carboxylic acid cyanomethyl ester Example 6 was prepared from Intermediate 6 using a method similar to that described for Example 4. LCMS retention time 3.48 min, m/z 576 MH+ Example 7: 6α,9α-Difluoro-11ß-hydroxy-17α-(4-methoxybenzoyl)oxy-16 -methylo-3- oxo-androsta-1, 4-diene-17ß-carboxvlic acid cyanomethyl ester Example 7 was prepared from Intermediate 7 using a method similar to that described for Example 4. LCMS retention time 3.53 min, m/z 570 MH+ Example 8: 17a- (4-Cyanobenzoyl)oxy-6α,9α-difluoro-11ß-hydroxy-16α-methy l-3- oxo-androsta-1, 4-diene-17ß-carboxylic acid cyanomethyl ester Example 8 was prepared from Intermediate 8 using a method similar to that described for Example 4. LCMS retention time 3. 44 min, mlz 565 MH+ Example 9 : 7α-(Cyclopentylmethylcarbonyl)oxy-6α,9α-difluoro-11ß-hyd roxy-16α- methyl-3-oxo-androsta-1 4-diene-17a-carboxylic acid cyanomethyl ester Example 9 was prepared from Intermediate 9 using a method similar to that described for Example 4. LCMS retention time 3.69 min, mlz 546 MH+ <BR> <BR> <BR> <BR> <BR> <BR> <BR> Example 10: 6α,9α-Difluroo-17α-(3,3-dimethylbutanoyl)oxy-11ß-hydroxy -16α-methyl- 3-oxo-androsta-1,4-diene-17ß-carboxylic acid cyanomethyl ester Example 10 was prepared from Intermediate 10 using a method similar to that described for Example 4. LCMS retention time 3. 60 min, m/z 534 MH+ Example 11 : 6α, 9a,-Difluoro-11 a-hvdroxy-17a- (2-isopropyl-1, 3-thiazole-4- carbonyl) oxv-16a-methyl-3-oxo-androsta-1, 4-diene-17a-carboxylic acid cyanomethyl ester Example 11 was prepared from Intermediate 11 using a method similar to that described for Example 4. LCMS retention time 3.50 min, rnlz 589 MHq

Example 12: 6a. 9a-Difluoro-11ß-hydroxy-16a-methvl-3-oxo-17a-(quinoline-2- carbonvl) oxv-androsta-1. 4-diene-17ß-carboxylic acid cyanomethyl ester Example 12 was prepared from Intermediate 12 using a method similar to that described for Example 4. LCMS retention time 3.61 min, m/z 591 MH+ Example 13: 6a. 9α-Difluoro-11ß-hydroxy-16α-methyl-3-oxo-17α-(5-trifluor omethyl- furan-2-carbonvl) oxv-androsta-1. 4-diene-1 70-carboxylic acid cyanomethvl ester Example 13 was prepared from Intermediate 13 using a method similar to that described for Example 4. LCMS retention time 3.72 min, m/z 598 MH+ Example 14: 6a. 9a-Difluoro-1 13-hvdroxv-16a-methvl-17a- (5-methvlsulphonyl- thiophene-2-carbonvl) oxy-3-oxo-androsta-1, 4-diene-17ß-carboxylic acid cyanomethyl ester Example 14 was prepared from Intermediate 14 using a method similar to that described for Example 4. LCMS retention time 3.29 min, m/z 624 MH+ <BR> <BR> <BR> <BR> <BR> Example 15: 6α,9α-Difluoro-11ß-hydroxy-16α-methyl -17α-(5-methylthio-thiophene-2- carbonyl) oxy-3-oxo-androsta-1, 4-diene-170-carboxylic acid cyanomethyl ester Example 15 was prepared from Intermediate 15 using a method similar to that described for Example 4. LCMS retention time 3.64 min, m/z592 MH'' Example 16 : 6α, 9α-Difluoro-17α-(5-ethyl-isoxazole-3-carbonyl)oxy-11ß-hyd roxy-16α- methvI-3-oxo-androsta-1. 4-diene-17ß-carboxylic acid cyanomethyl ester Example 16 was prepared from Intermediate 16 using a method similar to that described for Example 4. LCMS retention time 3.44 min, m/z 559 MH+ Example 17 : 9α-Fluroo-11ß-hydroxy-16ß-methyl-3-oxo-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl) oxy-androsta-1,4-diene-17ß-carboxylic acid cyanomethyl ester Example 17 was prepared from Intermediate 17 using a method similar to that described for Example 4. LCMS retention time 3.77 min, m/z 542 MH+ Example 18: 6α,9α-Difluroo-11ß-hydroxy-16α-methyl-3-oxo-17α-(2,2,3, 3- tetramethycyclopropylcarbonyl) oxy-androst-4-ene-17ß-carboxylic acid cyanomethyl ester

A solution of Example 4 (1.8g, 3. 2mmol) and Wilkinson's catalyst (0.5g, 0. 54mmol) in a 2: 1 mixture of toluene and ethyl acetate (130ml) was hydrogenated for 5 days. A further batch of catalyst (0.5g) was added after 1 day. The solution was evaporated and the residue was chromatographed on a 100g silicia cartridge using firstly a cyclohexane : ethyl acetate 0-30% gradient over 15min and then cyclohexane : ethyl acetate 30% for 10min. Appropriate fractions were combined and evaporated to give title compound as a white solid (400mg): LCMS retention time 3.73 min, m/z 579 MNH4+ ~ Example 19: 17a- (5-Chloro-4-methoxv-thiophene-3-carbonvl) oxy-6a, 9a-difluoro-11 a- hvdroxy-16a-methvl-3-oxo-androsta-1, 4-diene-17 (3-carboxvlic acid cyanomethyl ester Example 19 was prepared from Intermediate 18 using a method similar to that described for Example 4. LCMS retention time 3.57 min, m/z 610, 612 MH+ Example20 : 17α-(2,2-Dichloro-3,3-dimethylclopropylcarbonyl)oxy-6α,9α -difluoro- 11ß-hydroxy-16α-methylo-3-oxo-androsta-1,4-diene-17ß-carb oxylic acid cyanomethyl ester Example 20 was prepared from Intermediate 19 using a method similar to that described for Example 4. LCMS retention time 3. 62 min, mlz 600, 602, 604 MH+ <BR> <BR> <BR> <BR> <BR> Example 21: 17α-(2,2-Dichloro-3,3-dimethylclopropylcarbonyl)oxy-6α,9α -difluoro-<BR> <BR> <BR> <BR> 11 j3-hvdroxv-16a-methyt-3-oxo-androsta-1. 4-diene-17B-carbothioic acid S- cyanomethyl ester Example 21 was prepared from Intermediate 20 using a method similar to that described for Example 1. LCMS retention time 3. 58 min, m/z 616, 618, 620 MH+ Example 22: 17α- (Cvclohexvlcarbonvl) oxv-6a, 9a-difluoro-11 i-hydroxv-16a-methvl- 3-oxo-androsta-1 4-diene-1 7ß-carbothioic acid S-cyanomethyl ester Example 22 was prepared from Intermediate 21 using a method similar to that described for Example 1. LCMS retention time 3.60 min, m/z 562 MH+

Example 23: 6α, 9α-Difluoro-11ß-hydroxy-16α-methyl -17α-(5-methylsulphonyl- thiophene-2-carbonyl) oxy-3-oxo-androsta-1, 4-diene-17ß-carbothioic acid S- cyanomethyl ester Example 23 was prepared from Intermediate 22 using a method similar to that described for Example 1. LCMS retention time 3.30 min, m/z 640 MH+ Example 24: 6cc, 9a-Difluoro-1113-hydroxv-16a-methvl-3-oxo-17a- (5-trifluoromethvl- furan-2-carbonvl) oxv-androsta-1. 4-diene-17ß-carbothioic acid S-cyanomethyl ester Example 24 was prepared from Intermediate 23 using a method similar to that described for Example 1. LCMS retention time 3.60 min, m/z 614 MH+ Example 25: 6α,9α-Difluoro-17α-(3-(difluoromethylthio)benzoyl)oxy-11 -hydroxy- 16a-methyl-3-oxo-androsta-1, 4-diene-17ß-carbothioic acid S-cyanomethyl ester Example 25 was prepared from Intermediate 24 using a method similar to that described for Example 1. LCMS retention time 3.65 min, m/z 638 MH+ Pharmacological Activity Pharmacological activity may be assessed in functional in vitro assays of glucocorticoid agonist activity.

The functional assay based on that described by K. P. Ray et al., Biochem J. (1997), 328, 707-715 provides a measure of transrepressive activity of a glucocorticoid agonist. A549 cells stably transfected with a reporter gene containing the NF-#B responsive elements from the ELAM gene promoter coupled to sPAP (secreted alkaline phosphatase) are treated with test compounds at appropriate doses for 1 hour at 37°C. The cells are then stimulated with tumour necrosis factor (TNF, 10ng/ml) for 16 hours, at which time the amount of alkaline phosphatase produced is measured by a standard colourimetric assay. Dose response curves are constructed from which EC50 values may be estimated.

The ECSO values for compounds of Examples 1 to 25 were < 10nM.

EC5o values of <1 nM were observed for Examples 1 to 11,14 to 22 and 25 EC50 values of < 0. 1 nM were observed for Examples 4, 8,15 and 20 The functional assay based on that described by R. J. H. Austin et al., Eur Resp J. (2002), 20,1386-1392 measures the ability of compounds to directly transactivate gene expression. A549 cells stably transfected with a reporter gene containing the glucocorticoid responsive region of the mouse mammary tumour virus long terminal repeat (MMTV-LTR) coupled to renilla luciferase were treated with test compounds at appropriate doses for 6 hour at 37°C. The amount of luciferase activity present within the cells is then determined by measuring the light emitted following incubation with a suitable substrate. Dose response curves were constructed from which EC5o values were estimated and from which maximal responses are calculated relative to Dexamethasone (100%).

Compounds of Examples 1 to 25 showed maximal responses of <35% in this assay.

Compounds of Examples 1,2, 4,5, 6,9 to 11,13 and 15 to 25 showed maximal responses of <20 % in this assay.

Compounds of Examples 2 and 4 showed maximal responses of <5% in this assay.

Assay for progesterone receptor activity The human breast cancer cell line T47D has been reported to upregulate an endogenous alkaline phosphatase in response to progestins (Di Lorenzo et al., Cancer Research (1991) 5 «, 4470-4475 T47D cells were seeded into 96 well plates at a density of 1x105 cells aer well and grown overnight at 37°C. Steroids were dissolved in DMSO, added to the cells (final DMSO concentration 0. 7%), and incubated for 24 hours at 37°C. The cells were then washed with with and and with RIPA buffer (1% IGEPAL, 0.5% Na deoxycholate, 0. 1% SDS in phosphate buffered saline). Alkaline phosphatase activity was measured spectrophotometrically (405nm) using p-nitrophenylphosphate (1. 5mg/ml) as a substrate dissolved in 1M diethanolamine, 0.28M NaCI, 0.5mM MgCI2 Dose response curves were constructed from which EC50 values were estimated.

The EC5o values for compounds of Examples 4,5, 8,11, 18,20, 23,24 and 25 in this assay were >100nM Throughout the specification and the claims which follow, unless the context requires otherwise, the word'comprise', and variations such as'comprises'and'comprising', will be understood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or group of integers or steps.

The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims.

The patents and patent applications described in this application are herein incorporated by reference.