Pharmaceutical compositions containing micronized bicyclic drugs

A pharmaceutical composition comprising a compound of Formula I or Formula II below in particulate form, said composition having a particle size distribution such that the median value of the volume mean diameter is within the range of from 350 to 700 nm:

• 3
• wherein:
• either Y is N and R2 is hydrogen, or Y is C—R1
• where:
• either one of R1 and R2 is hydrogen and the other is selected from the class of hydrogen, C3-8 cycloalkyl, C1-6 alkyl optionally interupted by oxygen or substituted by hydroxy, C1-6 alkoxy or substituted aminocarbonyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkoxy, nitro, cyano, halo, trifluoromethyl, CF3S, or a group CF3—A—, where A is —CF2—, —CO—, —CH2— or CH(OH), trifluoromethoxy, C1-6 alkylsulphinyl, C1-6 alkylsulphonyl, C1-6 alkoxysulphinyl, C1-6 alkoxysulphonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, arylsulphinyl, heteroarylsulphinyl, arylsulphonyl, heteroarylsulphonyl in which any aromatic moiety is optionally substituted, C1-6 alkylcarbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl, C1-6 alkyl-thiocarbonyloxy, 1-mercapto C2-7 alkyl, formyl, or aminosulphinyl, aminosulphonyl or aminocarbonyl, any amino moiety being optionally substituted by one or two C1-6 alkyl groups, or C1-6 alkylsulphinylamino, C1-6 alkylsulphonylamino,C1-6 alkoxysulphinylamino or C1-6 alkoxysulphonylamino, or ethylenyl terminally substituted by C1-6 alkylcarbonyl, nitro or cyano, or —C(C1-6 alkyl)NOH or —C(C1-6 alkyl)NNH2, or one of R1 and R2 is nitro, cyano or C1-3 alkylcarbonyl and the other is methoxy or amino optionally substituted by one or two C1-6 alkyl or by C2-7 alkanoyl;
• one of R3 and R4 is hydrogen or C1-4 alkyl and the other is C1-4 alkyl or R3 and R4 together are C2-5 polymethylene;
• R5 is C1-6 alkylcarbonyloxy, benzoyloxy, ONO2, benzyloxy, phenyloxy or C1-6 alkoxy and R6 and R9 are hydrogen or R5 is hydroxy and R6 is hydrogen or C1-2 alkyl and R9 is hydrogen;
• R7 is fluorophenyl;
• R8 is hydrogen or C1-6 alkyl;
• the R8—N—CO—R7 group being trans to the R5 group;
• and X is oxygen or NR10 where R10 is hydrogen or C1-6alkyl;
• and
• 4
• wherein:
• either Y is N and R2 is hydrogen, or Y is C—R1
• where:
• either one of R1 and R2 is hydrogen and the other is selected from the class of hydrogen, C3-8 cycloalkyl, C1-6 alkyl optionally interrupted by oxygen or substituted by hydroxy, C1-6 alkoxy or substituted aminocarbonyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkoxy, nitro, cyano, halo, trifluoromethyl, CF3S, or a group CF3—A—, where A is —CF2—, —CO—, —CH2—, CH(OH), SO2, SO, CH2—O, or CONH, or a group CF2H—A′— where A′ is oxygen, sulphur, SO, SO2, CF2 or CFH;
• trifluoromethoxy, C1-6 alkylsulphinyl, perfluoro C2-6 alkylsulphonyl, C1-6 alkylsulphonyl, C1-6 alkoxysulphinyl, C1-6 alkoxysulphonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulphinyl, heteroarylsulphinyl, arylsulphonyl, heteroarylsulphonyl in which any aromatic moiety is optionally substituted, C1-6 alkylcarbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl, C1-6 alkyl-thiocarbonyloxy, 1-mercapto C2-7 alkyl, formyl, or aminosulphinyl, aminosulphonyl or aminocarbonyl, any amino moiety being optionally substituted by one or two C1-6 alkyl groups, or C1-6 alkylsulphinylamino, C1-6 alkylsulphonylamino,C1-6 alkoxysulphinylamino or C1-6 alkoxysulphonylamino, or ethylenyl terminally substituted by C1-6 alkylcarbonyl, nitro or cyano, or —C(C1-6 alkyl)NOH or —C(C1-6 alkyl)NNH2, or one of R1 and R2 is nitro, cyano or C1-3 alkylcarbonyl and the other is methoxy or amino optionally substituted by one or two C1-6 alkyl or by C2-7 alkanoyl;
• or R1 and R2 together are —(CH2)4— or —CH═CH—CH═CH—, or form an optionally substituted triazole or oxadiazole ring;
• one of R3 and R4 is hydrogen or C1-4 alkyl and the other is C1-4 alkyl, CF3 or CH2 Xa where Xa is fluoro, chloro, bromo, iodo, C1-4 alkoxy, hydroxy, C1-4 alkylcarbonyloxy, —S—C1-4 alkyl, nitro, amino optionally substituted by one or two C1-4 alkyl groups;
• cyano or C1-4 alkoxycarbonyl or R3 and R4 together are C2-5 polymethylene optionally substituted by C1-4 alkyl;
• R5 is C1-6 alkylcarbonyloxy, benzoyloxy, ONO2, benzyloxy, phenyloxy or C1-6 alkoxy and R6 and R9 are hydrogen or R5 is hydroxy and R6 is hydrogen or C1-2 alkyl and R9 is hydrogen;
• R7 is heteroaryl or phenyl;
• both of which are optionally substituted one or more times independently with a group or atom selected from chloro, fluoro, bromo, iodo, nitro, amino optionally substituted once or twice by C1-4 alkyl, cyano, azido, C1-4 alkyl, C1-4 alkoxy, trifluoromethoxy and trifluoromethyl;
• R8 is hydrogen;
• C1-6 alkyl, OR9 or NHCOR10 wherein R9 is hydrogen, C1-6 alkyl, formyl, C1-6 alkanoyl, aroyl or aryl-C1-6 alkyl and R10 is hydrogen, C1-6 alkyl, C1-6 alkoxy, mono or di C1-6 alkyl amino, amino, amino-C1-6 alkyl, hydroxy-C1-6 alkyl, halo-C1-6 alkyl, C1-6 acyloxy-C1-6 alkyl, C1-6 alkoxycarbonyl-C1-6-alkyl, aryl or heteroaryl;
• the R8—N—CO—R7 group being cis to the R5 group;
• and X is oxygen or NR10 where R10 is hydrogen or C1-6 alkyl.