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Last Updated: March 29, 2024

Claims for Patent: 7,101,866


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Summary for Patent: 7,101,866
Title:Anti-inflammatory androstane derivative
Abstract:According to one aspect of the invention, there is provided a compound of formula (I) ##STR00001## and solvates thereof. There are also provided compositions containing the compound, processes for preparing it, and its use in therapy.
Inventor(s): Biggadike; Keith (Stevenage, GB), Coote; Steven John (Stevenage, GB), Nice; Rosalyn Kay (Stevenage, GB)
Assignee: Glaxo Group Limited (Greenford, GB)
Application Number:09/958,050
Patent Claims: 1. A compound of formula (I) ##STR00026## or solvates thereof.

2. A compound of formula (I) as defined in claim 1 in unsolvated form.

3. A compound of formula (I) ##STR00027## in unsolvated form in the form of Form 1 polymorph, said Form 1 polymorph characterized by an XRPD profile having a peak at around 18.9 degrees 2Theta.

4. A compound of formula (I) ##STR00028## in unsolvated form in the form of Form 2 polymorph, said Form 1 polymorph characterized by an XRPD profile having a peak at around 18.9 degrees 2Theta.

5. A compound of formula (I) ##STR00029## in unsolvated form in the form of Form 3 polymorph, said Form 1 polymorph characterized by an XRPD profile having a peak at around 18.9 degrees 2Theta.

6. A compound of formula (I) as defined in claim 1 as a crystalline solid in the form of an essentially stoichiometric solvate with isopropanol.

7. A compound of formula (I) as defined in claim 1 as a crystalline solid in the form of an essentially stoichiometric solvate with methylethylketone.

8. A pharmaceutical composition comprising a compound of formula (I) or a physiologically acceptable solvate thereof as defined in claim 1 in admixture with one or more physiologically acceptable diluents or carriers.

9. A pharmaceutical formulation according to claim 8 which is non-pressurised and adapted to be administered as a dry powder topically to the lung via the buccal cavity.

10. A pharmaceutical formulation according to claim 8 which contains lactose or starch as the diluent or carrier.

11. A pharmaceutical formulation according to claim 8 which is non-pressurised and adapted to be administered topically to the nasal cavity.

12. A pharmaceutical formulation according to claim 11 which contains water as the diluent or carrier.

13. A pharmaceutical aerosol formulation comprising a compound of formula (I) or a physiologically acceptable solvate thereof as defined in claim 1, and a fluorocarbon or hydrogen-containing chlorofluorocarbon as propellant, optionally in combination with a surfactant and or a cosolvent.

14. A pharmaceutical aerosol formulation according to claim 13 which does not comprise particulate medicament, a propellant and a stabiliser comprising a water addition and does not comprise particulate medicament, a propellant and a stabiliser comprising an amino acid.

15. A pharmaceutical aerosol formulation according to claim 13 which comprises a compound of formula (I) or a physiologically acceptable solvate thereof, and a fluorocarbon or hydrogen-containing chlorofluorocarbon as propellant and a suspending agent which is soluble in the propellant.

16. A pharmaceutical aerosol formulation according to claim 15 wherein the suspending agent is an oligolactic acid.

17. A pharmaceutical aerosol formulation according claim 13 wherein the propellant is selected from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof.

18. A pharmaceutical aerosol formulation according to claim 13 which consists essentially of a compound of formula (I) or a physiologically acceptable solvate thereof, optionally in combination with another therapeutically active agent and a propellant selected from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof.

19. A pharmaceutical composition according to claim 8 which further comprises another therapeutically active agent.

20. A pharmaceutical composition comprising a combination of a compound of formula (I) or a physiologically acceptable solvate thereof according to claim 1 together with a PDE4 inhibitor together with a physiologically acceptable diluent or carrier.

21. 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 a physiologically acceptable solvate thereof as defined in claim 1.

22. A process for preparing a compound of formula (I) according to claim 1 or a solvate thereof which comprises alkylation of a compound of formula (II) ##STR00030## or a salt thereof.

23. A process according to claim 22 wherein alkylation is performed by reacting the compound of formula (II) or a salt thereof with a fluoromethyl halide.

24. A process for preparing a compound of formula (I) as unsolvated Form 1 polymorph according to claim 3 which comprises: (a) Crystallising the compound of formula (I) in the presence of a non-solvating solvent; or (b) Desolvating a compound of formula (I) in solvated form.

25. A process for preparing a compound of formula (I) as unsolvated Form 1 polymorph according to claim 3 which comprises dissolving compound of formula (I) in methylisobutylketone, ethyl acetate or methyl acetate and producing compound of formula (I) as unsolvated Form 1 by addition of a non-solvating anti-solvent.

26. A compound of formula (II) ##STR00031## or a salt thereof.

27. A compound of formula (II) as defined in claim 26 in the form of a solid crystalline salt.

28. A compound of formula (II) according to claim 27 in the form of the diisopropylethylamine salt.

29. A process a process for preparing a compound of formula (II) according to claim 26 which comprises: (a) reacting a compound of formula (III) ##STR00032## with an activated derivative of 2-furoic acid as in an amount of at least 2 moles of the activated derivative per mole of compound of formula (III) to yield a compound of formula (IIA) ##STR00033## ; and (b) removal of the sulphur-linked 2-furoyl moiety from compound of formula (IIA) by reaction of the product of step (a) with an organic primary or secondary amine base capable of forming a water soluble 2-furoyl amide.

30. A process for preparing a compound of formula (II) according to claim 29 which further comprises the steps of: (c1) when the product of step (b) is dissolved in a substantially water immiscible organic solvent, purifying the compound of formula (II) by washing out the amide by-product from step (b) with an aqueous wash, or (c2) when the product of step (b) is dissolved in a water miscible solvent, purifying the compound of formula (II) by treating the product of step (b) with an aqueous medium so as to precipitate out pure compound of formula (II) or a salt thereof.

31. A process for preparing a compound of formula (II) ##STR00034## which comprises: (a) reacting a compound of formula (III) ##STR00035## with an activated derivative of 2-furoic acid in an amount of at least 2 moles of activated derivative per mole of compound of formula (III) to yield a compound of formula (IIA) ##STR00036## ; and (b) removal of the sulphur-linked 2-furoyl moiety from compound of formula (IIA) by reaction of the product of step (a) with a further mole of compound of formula (III) to give two moles of compound of formula (II).

32. A compound of formula (IIA) ##STR00037##

33. A compound of formula (IXA) ##STR00038## wherein X represents halogen.

34. A compound of formula (XV) ##STR00039## wherein P represents a hydroxy protecting group.

35. A compound of formula (XVI) ##STR00040##

36. A compound of formula (XVII) ##STR00041## or a salt thereof wherein P represents a hydroxy protecting group.

37. A compound of formula (XX) ##STR00042## or a salt thereof or a derivative wherein the 11-carbonyl group is masked.

38. A compound of formula (XXIII) ##STR00043## wherein L represents a leaving group other than fluorine.

39. A process for preparing compound of formula (I) in unsolvated Form 2 polymorph as claimed in claim 4 which comprises dissolving compound of formula (I) in unsolvated form in methanol or dry dichloromethane and recrystallising the compound of formula (I) as unsolvated Form 2 polymorph.

40. A process for preparing compound of formula (I) in solvated Form 3 polymorph as claimed in claim 5 which comprises dissolving compound of formula (I) or a solvate thereof in dichloromethane in the presence of water and recrystallising the compound of formula (I) as unsolvated Form 3 polymorph.

41. An process for preparing a compound of formula (I) as defined in claim 1 or a solvate thereof which comprises reacting a compound of formula (VI) ##STR00044## with a fluorine source.

42. A process for preparing a compound of formula (I) or a solvate thereof which comprises: (a) providing a compound of formula (I) ##STR00045## or a solvate thereof in which the 11-.beta.-hydroxy group is protected or masked and (b) deprotecting or unmasking said compound to yield the compound of formula (I) or a solvate thereof.

43. A process according to claim 42 wherein the 11-.beta.-hydroxy group is protected which comprises deprotecting a compound of formula (XV) ##STR00046## wherein P represents a hydroxy protecting group.

44. A process according to claim 42 wherein the 11-.beta.-hydroxy group is masked which comprise reduction of a compound of formula (XVI) ##STR00047## or a derivative wherein the 11-carbonyl group is masked.

45. A process for the preparation of a compound of formula (I) as defined in claim 1 or a solvate thereof which comprises reaction of a compound of formula (XXIII) ##STR00048## wherein L represents a leaving group with a fluorine source.

46. A process for the preparation of a compound of formula (I) or a solvate thereof which comprises: (a) providing a derivative of a compound of formula (I) ##STR00049## or a solvate thereof in which the 3-carbonyl group is protected or masked, and (b) deprotecting or unmasking said derivative of a compound of formula (I).

47. A process for preparing a compound of formula (II) ##STR00050## which comprises treating a compound of formula (X) ##STR00051## with a reagent suitable for converting a carboxylic acid to a carbothioic acid.

48. The method for the treatmentof a human or animal subject with an inflammatory and/or allergic condition according to claim 21, wherein said effective amount of the compound of formula (I) or a physiologically acceptable solvate thereof is administered topically to said human or animal subject.

49. The method for the treatment of a human or animal subject with an inflammatory and/or allergic condition according to claim 21, wherein said effective amount of the compound of formula (I) or a physiologically acceptable solvate thereof is administered topically as a dry powder to the lung via the buccal cavity.

50. The method for the treatment of a human or animal subject with an inflammatory and/or allergic condition according to claim 21, wherein said effective amount of the compound of formula (I) or a physiologically acceptable solvate thereof is administered once per day.

51. A method for the treatment of at least one condition selected from the group consisting of skin disease inflammatory condition of the nose, throat or lungs, inflammatory bowel condition, rheumatoid arthritis, conjunctiva and conjunctivitis in a human or animal subject, which comprises administering an effective amount of the compound of formula (I)_ or a physiologically acceptable solvate thereof as defined in claim 1 to said human or animal subject in need therof for the treatment of said at least one condition.

52. The method of treatment as recited in claim 51, wherein the skin disease is at least one selected from the group consisting of eczema, psoriasis, allergic dermatitis neurodermatitis, pruritis and hypersensitivity reactions.

53. The method of treatment as recited in claim 51, wherein the inflammatory condition of the nose, throat or lungs is at least one selected from the group consisting of asthma, rhinitis, nasal polyps, chronic obstructive pulmonary diseas, interstitial lung disease and fibrosis.

54. The method of treatment as recited in claim 51, wherein the inflammatory condition of the nose, throat or lungs is asthma.

55. The method of treatment as recited in claim 51, wherein the inflammatory condition of the nose, throat or lungs is rhinitis.

56. The method of treatment as recited in claim 51, wherein the inflammatory condition of the nose, throat or lungs is chronic obstructive pulmonary diseas.

57. The method of treatment as recited in claim 51, wherein the inflammatory bowel condition is at least one selected from the group consisting of ulcerative colitis and Crohn's disease.

58. The method of treatment as recited in claim 51, wherein said compound of formula (I) or a physiologically acceptable solvate thereof is administered by inhalation or by nebulisation.

59. The method of treatment as recited in claim 51, whreein said compound of formula (I) or a physiologically acceptable solvate thereof is administered orally, buccally, sublingually, parenterally, locally or rectally.

60. The method of treatment of a human or animal subject with an inflammatory and/or allergic condition according to claim 51, wherein said effective amount of the compound of formula (I) or a physiologically acceptable solvate thereof is administered topically to said human or animal subject.

61. The method for the treatment of a human or animal subject with an inflammatory and/or allergic condition according to claim 51, wherein said effective amount of the compound of formula (I) or a physiologically acceptable solvate thereof is administered topically as a dry powder to the lung via the buccal cavity.

62. The method for the treatment of a human or animal subject with an inflammatory and/or allergic condition according to claim 51, wherein said effective amount of the compound of formula (I) or a physiologically acceptable solvate thereof is administered once per day.

63. The pharmaceutical composition according to claim 8 or a physiologically acceptable solvate thereof, wherein the composition is selected from the group consisting of an ointment, lotion, gel, foam, preparation for delivery by transdermal patch, powder, spray, aerosol, capsule or cartridge for use in an inhaler or insufflator or drop, solution or suspension for nebulisation, suppositories, pessaries, retention enemas, chewable or suckable tablets or pellets, liposome preparation and microencapsulation preparation.

64. The pharmaceutical composition according to claim 8 or a physiologically acceptable solvate thereof, wherein the composition is a dry powder or spray.

65. The phamaceutical composition according to claim 64 or a physiologically acceptable solvate thereof, wherein the composition is a dry powder.

66. The pharmaceutical composition according to claim 64 or a physiologically acceptable solvate thereof, wherein the composition is a spray.

67. The pharmaceutical composition according to claim 8, wherein said compound of formula (I) or a physiologically acceptable solvate thereof is present in the amount of 0.001 to 10% by weight of said composition.

68. The pharmaceutical composition according to claim 19, wherein said another therapeutically active agent is an anti-histamine, anti-inflammatory agent or antiinfective agent.

69. The pharmaceutical composition to claim 68, wherein said anti-histamine is methapyrilene or loratadine, said anti-inflammatory agent is an NSAID and said antifective agent is an antibiotic or antiviral.

70. The pharmaceutical composition according to claim 20, wherein the PDE4 inhibitor is at least one selected from the group consisting of (R)-(+)- 1-(4-brornobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2- pyrrodlidone; (R)-(+)-1- (4-bromobenzyl)4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone; 3- 2-pyrrolidone; cis 4-cyano-4-(3-cyclopentyloxy-4-difluoromethoxyphenyl)cyclohexan-1-ol]; (R)-(+)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate; (S)-(-)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate; and 2-carbomethoxy-4-cyano-4(3-cyclopropylmethoxy-4-difluoromethoxypheny)cycl- ohexan-1-one.

71. An inhaler comprising a compound of formula (I) as defined in claim 1 or a physiologically acceptable solvante thereof.

72. The inhaler of claim 71, further comprising propellant.

73. The inhaler of claim 71, further comprising at least one excipient selected from the group consisting of surfactant and cosolvent. 74.The inhaler of claim 71, wherein said compound of formula (I) is retained in a pressurized canister closed with a valve.

75. The inhaler of claim 71, wherein said compound of formula (I) has a particle size in the range of 1-10.mu.m.

76. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 3 in admixture with one or more physiologically acceptable diluents or carriers.

77. A pharmaceutical formulation according to claim 76 which is non-pressurized and adapted to be administered as a dry powder topically to the lung via the buccal cavity.

78. A pharmaceutical formulation according to claim 76 which is contains lactose or starch as the diluent or carrier.

79. A pharmaceutical formulation according to claim 76 which is non-pressurized and adapted to be administered topically to the nasal cavity.

80. A pharmaceutical formulation according to claim 79 which contains water as the diluent or carrier.

81. A pharmaceutical aerosol formulation comprising a compound of formula (I) as defined in claim 3 and a fluorocarbon or hydrogen containing chlorofluorocarbon as propellant, optionally in combination with a surfactant.

82. A pharmaceutical aerosol formulation according to claim 81 which does not comprise particulate medicament, a propellant and a stabiliser comprising a water addition and does not comprise particulate medicament, a propellant and a stabiliser comprising an amino acid.

83. A pharmaceutical aerosol formulation according to claim 81 which comprises a compound of formula (I) and a fluorocarbon or hydrogen- containing chlorofluorocarbon as propellant and a suspending agent which is soluble in the propellant.

84. A pharmaceutical aerosol formulation according to claim 83 wherein the suspending agent is an oligolactic acid.

85. A pharmaceutical aerosol formulation according claim 81 wherein the propellant is selected from 1, 1, 1, 2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro- n-propane and mixtures thereof.

86. A pharmaceutical aerosol formulation according to claim 82 which consists essentially of a compound of formula (I) optionally in combination with another therapeutically active agent and a propellant selected from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof.

87. A pharmaceutical composition according to claim 76 which further comprises another therapeutically active agent.

88. A pharmaceutical composition according to claim 87 in which said another therapeutically active agent is a .beta..sub.2-adrenoreceptor agonist.

89. A pharmaceutical composition comprising a combination of a compound of formula (I) according to claim 3 together with a PDE4inhibitor together with physiologically acceptable diluent or carrier.

90. A method for the treatment of 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) as defined of in claim 3.

91. The method for the treatment of a human or animal subject with an inflammatory and/or allergic condition according to claim 90, wherein said effective amount of the compound of formula (I) is administered topically to said human or animal subject.

92. The method for the treatment of a human or animal subject with an inflammatory and/or allergic condition according to claim 90, wherein said effective amount of the compound of formula (I) is administered topically as a dry powder to the lung via the buccal cavity.

93. The method for the treatment of human or animal subject with an inflammatory and/or allergic condition according to claim 90, wherein said effective amount of the compound of formula (I) is administered once per day.

94. A method for the treatment of at least one condition selected from the group consisting of skin disease, inflammatory condition of the nose, throat or lungs, inflammatory bowel condition, rheumatoid arthritis, conjunctiva and conjunctivitis in a human or animal subject, which comprises administering an effective amount of the compound of formula (I) as defined in claim 3 to said human or animal subject in need thereof for the treatment of said at least one condition.

95. The method of treatment as recited in claim 94, wherein the skin disease is at least one selected from the group consisting of eczema, psoriasis, allergic dermatitis neurodermatitis, pruritis and hypersensitivity reactions.

96. The method of treatment as recited in claim 94, wherein the inflammatory condition of the nose, throat or lungs is at least one selected from the group consisting of asthma, rhinitis, nasal polyps, chronic obstructive pulmonary disease, interstitial lung disease and fibrosis.

97. The method of treatment as recited in claim 94, wherein the inflammatory condition of the nose, throat or lungs is asthma.

98. The method of treatment as recited in claim 94, wherein the inflammatory condition of the nose, throat or lungs is rhinitis.

99. The method of treatment as recited in claim 94, wherein the inflammatory condition of the nose, throat or lungs is chornic obstructive pulmonary disease.

100. The method of treatment as recited of claim 94, wherein the inflammatory bowel condition is at least one selected from the group consisting of ulcerative colitis and Crohn's disease.

101. The method of treatment as recited in claim 94, wherein said compound of formula (I) is administered by inhalation or by nebulisation.

102. The method of treatment as recited in claim 94, wherein said compound of formula (I) is administered orally, buccally, sublingually, pareuterally, locally or rectally.

103. The method for the treatment of a human or animal subject with an inflammatory and/or allergic condition according to claim 94, wherein said effective amount of the compound of formula (I) is administered topically to said bunion or animal subject.

104. The method for the treatment of a human or animal subject with an inflammatory and/or allergic condition according to claim 94, wherein said effective amount of the compound of formula (I) is administered topically as a dry powder to the lung via the buccal cavity.

105. The method for the treatment of a human or animal subject with an inflammatory and/or allergic condition according to claim 94, wherein said effective amount of the compound of formula (I) is administered once per day.

106. The pharmaceutical composition according to claim 76, wherein the composition is selected from the group consisting of an ointment, lotion, gel, foam, preparation for delivery by tranadermal patch) powder, spray, aerosol, capsule or cartridge for use in an inhaler or insufilator or drop, solution or suspension for nebulisation, suppositories, peasants, retention onanias, chewable or suckable tablets or pellets, liposome preparation and microencapsulation preparation.

107. The phamaceutical composition according to claim 76, wherein the composition is a dry powder or spray.

108. The pharmaceutical composition according to claim 107, wherein the composition is a dry powder.

109. The pharmaceutical composition according to claim 107, wherein the composition is a spray.

110. The pharmaceutical composition according to claim 88, wherein said .beta..sub.2-adrenoreceptor agonist is at least one selected from the group consisting of salmeterol, salbutamol, formoterol, salmefamol, fenoterol and terbutaline and salts thereof.

111. The pharmaceutical composition according to claim 76, wherein said compound of formula (I) is present in the amount of 0.001 to 10% by weight of said composition.

112. The pharmaceutical composition according to claim 107, wherein said another therapeutically active agent is an anti-histamine, anti-inflammatory agent or antiinfective agent.

113. The pharmaceutical composition according to claim 112, wherein said anti-histamine is methapyrilene or loratadine, said anti-inflammatory agent is an ID and said antiinfective agent is an antibiotic or antiviral.

114. The pharmaceutical composition according to claim 89, wherein the PDE4 inhibitor is at least one selected from the group consisting of (R)-(=) 1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2- pyrrolidone; (R)-(+)-1- (4-bromobenzyl)4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone; 3- 2-pyrrolidone; cis 4-cyano-4-(3-cyclopentyloxy-4-difluoromethoxyphenyl)cyclohexan-1-ol]; (R)-(+)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate; (S)-(-)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate; and 2-carbomethoxy-4-cyano-4(3-cyclopropylmethoxy-4-difluoromethoxypheny)cycl- ohexan-1-one.

115. An inhaler comprising a compound of formula (I) as defined in claim 3.

116. The inhaler of claim 115, further comprising propellant.

117. The inhaler of claim 115, further comprising surfactant.

118. The inhaler of claim 115, wherein said compound of formula (I) is retained in a pressurized canister closed with a Valve.

119. The inhaler of claim 115, wherein said compound of formula (I) has a particle size in the range of 1-10 .mu.m.

120. A pharmaceutical composition comprising a compound of formula (1) as defined in claim 4 in admixture with one or more physiologically acceptable diluents or carriers.

121. A pharmaceutical formulation according to claim 120 which is non-pressurized and adapted to be administered as a dry powder topically to the lung via the buccal cavity.

122. A pharmaceutical formulation according to claim 120 which contains lactose or starch as the diluent or carrier.

123. A pharmaceutical formulation according to claim 120 which is non-pressurized and adapted to be administered topically to the nasal cavity.

124. A pharmaceutical formulation according to claim 123 which contains water as the diluent or carrier.

125. A pharmaceutical aerosol formulation comprising a compound of formula (I) as defined in claim 4 and a fluorocarbon or hydrogen- containing chlorofluorocarbon as propellant, optionally in combination with a surfactant.

126. A pharmaceutical aerosol formulation according to claim 125 which does not comprise particulate medicament, a propellant and a stabilizer comprising a water addition and does not comprise particulate medicament, a propellant and a stabilizer comprising an amino acid.

127. A pharmaceutical aerosol formulation according to claim 125 which comprises a compound of formula (I) and a fluorocarbon or hydrogen- containing chlorofluorocarbon as propellant and a suspending agent which is soluble in the propellant.

128. A pharmaceutical aerosol formulation according to claim 127 wherein the suspending agent is an oligolactic acid.

129. A pharmaceutical aerosol formulation according claim 125 wherein the propellant is selected from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3- heptafluoro-n-propane and mixtures thereof.

130. A phamaceutical aerosol formulation according to claim 125 which consists essentially of a compound of formula (I) optionally in combination with another therapeutically active agent and a propellant selected from 1,1,1,2- tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof.

131. A pharmaceutical composition according to claim 120 which further comprises another therapeutically active agent.

132. A pharmaceutical composition according to claim 131 in which said another therapeutically active agent is a .beta..sub.2-adrenoreceptor agonist.

133. A phamaceutical composition comprising a combination of a compound of formula (I) according to claim 4 together with a PDE4 inhibitor together with a physiologically acceptable diluent or carrier.

134. 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) as defined in claim 4.

135. The method for the treatment of a human or animal subject with an inflammatory and/or allergic condition according to claim 134, wherein said effective amount of the compound of formula (I) is administered topically to said human or animal subject.

136. The method for the treatment of a human or animal subject with an inflammatory and/or allergic condition according to claim 134, wherein said effective amount of the compound of formula (I) is administered topically as a dry powder to the lung via the buccal cavity.

137. The method for the treatment of a human or animal subject with an inflammatory and/or allergic condition according to claim 134, wherein said effective amount of the compound of formula (I) is administered once per day.

138. A method for the treatment of at least one condition selected from the group consisting of skin disease, inflammatory condition of the nose, throat or lungs, inflammatory bowel condition, rheumatoid arthritis conjunctiva and conjunctivitis in a human or animal subject, which comprises administering an effective amount of the compound of formula (I) as defined in claim 4 to said human or animal subject in need thereof for the treatment of said at least one condition.

139. The method of treatment as recited in claim 138, wherein the skin disease is at least one selected from the group consisting of eczema, psoriasis, allergic dermatitis neurodermatitis, pruritis and hypersensitivity reactions.

140. The method of treatment as recited in claim 138, wherein the inflammatory condition of the nose, throat or kings is at least one selected from the group consisting of asthma, rhinitis, nasal polyps, chronic obstructive pulmonary disease, interstitial lung disease and fibrosis.

141. The method of treatment as recited in claim 138, wherein the inflammatory condition of the nose, throat or lungs is asthma.

142. The method of treatment as recited in claim 138, wherein the inflammatory condition of the nose, throat or lungs is rhinitis.

143. The method of treatment as recited in claim 138, wherein the inflammatory condition of the nose, throat or lungs is chronic obstructive pulmonary disease.

144. The method of treatment as recited in claim 138, wherein the inflammatory bowel condition is at least one selected from the group consisting of ulcerative colitis and Crohn's disease.

145. The method of treatment as recited in claim 138, wherein said compound of formula (I) is administered by inhalation or by nebulisation.

146. The method of treatment as recited in claim 138, wherein said compound of formula (I) is administered orally, buccally, sublingually, parenterally, locally or rectally.

147. The method for the treatment of a human or animal subject with inflammatory and/or allergic condition according to claim 138, wherein said effective amount of the compound of formula (I) is administered topically to said human or animal subject.

148. The method for the treatment of a human or animal subject with inflammatory and/or allergic condition according to claim 138, wherein said effective amount of the compound of formula (I) is administered topically as a dry powder to the lung via the buccal cavity.

149. The method for the treatment of a human or animal subject with an inflammatory and/or allergic condition according to claim 138, wherein said effective amount of the compound of formula (I) is administered once per day.

150. The pharmaceutical composition according to claim 120, wherein the composition is selected from the group consisting of an ointment, lotion, gel, foam, preparation for delivery by transdermal patch, powder, spray, aerosol, capsule or cartridge for use in an inhaler or insufflator or drop, solution or suspension for nebulisation, suppositories, pessaries, retention enernas, chewable or suckable tablets or pellets, liposome preparation and microencapsulation preparation.

151. The pharmaceutical composition according to claim 120, wherein the composition is a dry powder or spray.

152. The phamaceutical composition according to claim 151, wherein the composition is a dry powder.

153. The pharmaceutical composition according to claim 151, wherein the composition is a spray.

154. The pharmaceutical composition according to claim 132, wherein said .beta..sub.2-adrenoreceptor agonist is at least one selected from the group consisting of salmeterol, salbutamol, formoterol, salmefamol, fenoterol and terbutaline and salts thereof.

155. The pharmaceutical composition according to claim 120, wherein said compound of formula (I) is present in the amount of 0.001 to 10% by weight of said composition.

156. The pharmaceutical composition according to claim 131, wherein said another therapeutically active agent is an anti-histamine, anti-inflammatory agent or antiinfective agent.

157. The pharmaceutical composition according to claim 156, wherein said anti-histamine is methapyrilene or loratadine, said anti-inflammatory agent is an NSAID and said antiinfective agent is an antibiotic or antiviral.

158. The pharmaceutical composition according to claim 133, wherein the PDE4 inhibitor is at least one selected from the group consisting of (R)-(+)- 1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2- pyrrolidone; (R)-(+)-1- (4-bromobenzyl)4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone; 3- (cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N2-cyano-S-methyl-isothioureido- ]benzyl)- 2-pyrrolidone; cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1- carboxylic acid]; cis-[4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)cyclohexan-1-ol]; (R)-(+)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate; (S)-(-)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate; and 2-carbomethoxy-4-cyano-4(3-cyclopropylmethoxy-4-difluoromethoxypheny)cycl- ohexan-1-one.

159. An inhaler comprising a compound of formula (I) as defined in claim 4.

160. The inhaler of claim 159, further comprising propellant.

161. The inhaler of claim 159, further comprising surfactant.

162. The inhaler of claim 159, wherein said compound of formula (I) is retained in a pressurized canister closed with a valve.

163. The inhaler of claim 159, wherein said compound of formula (I) has a particle size in the range of 1-10 .mu.m.

164. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 5 in admixture with one or more physiologically acceptable diluents or carriers.

165. A pharmaceutical formulation according to claim 164 which is non-pressurized and adapted to be administered as a dry powder topically to the lung via the buccal cavity.

166. A pharmaceutical formulation according to claim 164 which contains lactose or starch as the diluent or carrier.

167. A pharmaceutical formulation according to claim 164 which is non-pressurized and adapted to be administered topically to the nasal cavity.

168. A pharmaceutical formulation according to claim 167 which contains water as the diluent or corner.

169. A pharmaceutical aerosol formulation comprising a compound of formula (I) as defined in claim 5 and a fluorocarbon or hydrogen- containing chlorofluorocarbon as propellant, optionally in combination with a surfactant.

170. A phamaceutical aerosol formulation according to claim 169 which does not comprise particulate medicament, a propellant and a stabilizer comprising a water addition and does not comprise particulate medicament, a propellant and a stabilizer comprising an amino acid.

171. A pharmaceutical aerosol formulation according to claim 169 which comprises a compound of formula (I) and a fluorocarbon or hydrogen- containing chlorofluorocarbon as propellant and a suspending agent which is soluble in the propellant.

172. A phamaceutical aerosol formulation according to claim 171 wherein the suspending agent is an oligolactic acid.

173. A pharmaceutical aerosol formulation according claim 169 wherein the propellant is selected from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3- heptafluoro-n-propane and mixtures thereof.

174. A pharmaceutical aerosol formulation according to claim 169 which consists essentially of a compound of formula (I) optionally in combination with another therapeutically active agent and a propellant selected from 1.1,1,2- tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof.

175. A pharmaceutical composition according to claim 164 which further comprises another therapeutically active agent.

176. A pharmaceutical composition according to claim 175 in which said another therapeutically active agent is a .beta..sub.2-adrenoreceptor agonist.

177. A pharmaceutical composition comprising a combination of a compound of formula (I) according to claim 5 together with a PDE4 inhibitor together with a physiologically acceptable diluent or carrier.

178. 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) as defined in claim 5.

179. The method for the treatment of a human or animal subject with an inflammatory and/or allergic condition according to claim 178, wherein said effective amount of the compound of formula (I) is administered topically to said human or animal subject.

180. The method for the treatment of a human or animal subject with an inflammatory and/or allergic condition according to claim 178, wherein said effective amount of the compound of formula (I) is administered topically as a dry powder to the lung via the buccal cavity.

181. The method for the treatment of a human or animal subject with an inflammatory and/or allergic condition according to claim 178, wherein said effective amount of the compound of formula (I) is administered once per day.

182. A method for the treatment of at least one condition selected from the group consisting of skin disease, inflammatory condition of the nose, throat or lungs, inflammatory bowel condition, rheumatoid arthritis conjunctiva and conjunctivitis in a human or animal subject, which comprises administering an effective amount of the compound of formula (I) as defined in claim 5 to said human or animal subject in need thereof for the treatment of said at least one condition.

183. The method of treatment as recited in claim 182, wherein the skin disease is at least one selected from the group consisting of eczema, psoriasis, allergic dermatitis neurodermatitis, pruritis and hypersensitivity reactions.

184. The method of treatment as recited in claim 182, wherein the inflammatory condition of the nose, throat or lungs is at least one selected from the group consisting of asthma, rhinitis, nasal polyps, chronic obstructive pulmonary disease, interstitial lung disease and fibrosis.

185. The method of treatment as recited in claim 182, wherein the inflammatory condition of the nose, throat or lungs is asthma.

186. The method of treatment as recited in claim 182, wherein the inflammatory condition of the nose, throat or lungs is rhinitis.

187. The method of treatment as recited in claim 182, wherein the inflammatory condition of the nose) throat or lungs is chronic obstructive pulmonary disease.

188. The method of treatment as recited in claim 182, wherein the inflammatory bowel condition is at least one selected From the group consisting of ulcerative colitis and Crohn's disease.

189. The method of treatment as recited in claim 182, wherein said compound of formula (I) is administered by inhalation or by nebulisation.

190. The method of treatment as recited in claim 182, wherein said compound of formula (I) is administered orally, buccally, sublingually, parenterally, locally or rectally.

191. The method for the treatment of a human or animal subject with an inflammatory and/or allergic condition according to claim 182, wherein said effective amount of the compound of formula (I) is administered topically to said human or animal subject.

192. The method for the treatment of a human or animal subject with an inflammatory and/or allergic condition according to claim 182, wherein said effective amount of the compound of formula (I) is administered topically as a dry powder to the lung via the buccal cavity.

193. The method for the treatment of a human or animal subject with an inflammatory and/or allergic condition according to claim 182, wherein said effective amount of the compound of formula (I) is administered once per day.

194. The pharmaceutical composition according to claim 164, wherein the composition is selected from the group consisting of an ointment, lotion, gel, foam, preparation for delivery by transdernal patch, powder, spray, aerosol, capsule or cartridge for use in an inhaler or insufflator or drop, solution or suspension for nebulisation, suppositories, pessaries, retention enemas, chewable or suckable tablets or pellets, liposome preparation and microencapsulation preparation.

195. The pharmaceutical composition according to claim 164, wherein the composition is a dry powder or spray.

196. The pharmaceutical composition according to claim 195, wherein the composition is a dry powder.

197. The pharmaceutical composition according to claim 195, wherein the composition is a spray.

198. The pharmaceutical composition according to claim 176, wherein said .beta..sub.2-adrenoreceptor agonist is at least one selected from the group consisting of salmeterol, salbutamol, formoterol salmefamol, fenoterol and terbutaline and salts thereof.

199. The pharmaceutical composition according to claim 164, wherein said compound of formula (I) is present in the amount of 0.001 to 10% by weight of said composition.

200. The pharmaceutical composition according to claim 175, wherein said another therapeutically active agent is an anti-histamine, anti-inflammatory agent or antiinfective agent.

201. The phamaceutical composition according to claim 200, wherein said anti-histamine is methapyrilene or loratadine, said anti-inflammatory agent is an NSAID and said antiinfective agent is an antibiotic or antiviral.

202. The phamaceutical composition according to claim 177, wherein the PDE4 inhibitor is at least one selected from the group consisting of (R.)-(+)- 1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2- pyrrolidone; (R)-(+)-1- (4-bromobenzyl)4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone; 3- (cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N2-cyano-S-methyl-isothioureido- ]benzyl)- 2-pyrrolidone; cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1- carboxylic acid]; cis-[4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)cyclohexan-1-ol]; (R)-(+)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate; (S)-(-)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate; and 2-carbomethoxy-4-cyano-4(3-cyclopropylmethoxy-4-difluoromethoxypheny)cycl- ohexan-1-one.

203. An inhaler comprising a compound of formula (I) as defined in claim 5.

204. The inhaler of claim 203, further comprising propellant.

205. The inhaler of claim 203, further comprising surfactant.

206. The inhaler of claim 203, wherein said compound of formula (I) is retained in a pressurized canister closed with a valve.

207. The inhaler of claim 203, wherein said compound of formula (I) has a particle size in the range of 1-10 .mu.m.

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