| 摘要 |
1. A pharmaceutical composition comprising a compound of Formula I below wherein the R8-N-CO-R7 group being cis to the R5 group, or either Y is N and R2 is hydrogen, or Y is C-R1, 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, C1-6 alkylcarbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkylthiocarbonyl, C1-6 alkoxythiocarbonyl, C1-6 alkylthiocarbonyloxy, 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 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; and X is oxygen or NR10, where R10 is hydrogen or C1-6 alkyl; and/or wherein the R8-N-CO-R7 group being trans to the R5 group; either one of R1 and R2 is hydrogen and the other is selected from the class of hydrogen, CF3-A-, where A is SO2, SO, CH2-O, or CONH, or a group CF2H-A'-where A' is oxygen, sulphur, SO, SO2, CF2 or CFH; perfluoro C2-6 alkylsulphonyl, C1-6 alkylsulphonyl, C1-6 alkoxysulphinyl, C1-6 alkoxysulphonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, or R1 and R2 together are(CH2)4- or-CH = CH-CH = CH-, triazole or oxadiazole ring; one of R3 and R4 is hydrogen or C1-4 alkyl and the other is C1-4 alkyl, CF3 or CH2X<A> where X<A> 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; 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 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 alkylamino, amino, amino- C1-6 alkyl, hydroxy- C1-6 alkyl, C1-6 acyloxy- C1-6 alkyl, C1-6 alkoxycarbonyl-C1-6 alkyl, alkyl, aryl or heteroaryl; 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. 2. A composition according to claim 1 in which the particles of the compounds of Formula I are present as a monomodal distribution. 3. A composition according to claim 2 in which no more than 10% of the particles having a volume diameter of 280 nm or below, and no less than 90% of the particles having a volume diameter of 2000 nm or below. 4. A composition according to any one of claims 1 to 3 in which the median volume diameter is in the range of 450 to 550 nm. 5. A composition according to claim 4 in which 10% of particles have a volume diameter of 260 nm or below and 90% of particles have a volume diameter of 1450 nm or below. 6. A composition according to any one of claims 1 to 6 which is obtainable by wet milling compounds of Formula I as an aqueous dispersion. 7. A composition according to claim 6 which is obtainable by wet milling using a multi-chamber bead mill with single pass or recirculation of product between the chambers. 8. A composition according to claim 6 or 7 which is obtainable using ceramic beads of rare earth oxides as milling medium. 9. A composition according to claim 7 or 8 which is obtainable using a multichamber chamber mill in which the beads in one chamber are of a smaller diameter than the beads in the other chambers. 10. A composition according to claim 9 which is obtainable by using a range of bead sizes between 0.4mm and 1.25mm in each chamber. 11. A composition according to any one of claims 1 to 10 including a soluble carrier suitable as an excipient for spray drying. 12. A composition according to claim 10 in which the soluble carrier is mannitol. 13. A composition according to any one of claims 1 to 12 including a surfactant to maintain the particles in suspension during milling and on re-suspension. 14. A composition according to claim 13 in which the surfactant is sodium lauryl sulphate. 15. A composition according to any one of claims 1 to 14 including an anti-agglomeration agent effective after administration of a pharmaceutical formulation to a patient. 16. A composition according to claim 15 in which the anti-agglomeration agent is hydroxypropyl methylcellulose. 17. A process for preparing a particulate composition of a sparingly water-soluble drug substance which comprises wet milling the drug substance as an aqueous dispersion in a multi-chamber bead mill with circulation of product between the chambers, the aqueous dispersion including a soluble carrier suitable as an excipient for spray drying, a surfactant to maintain the particles in suspension on re-suspension, and an anti-agglomeration agent effective after administration of a pharmaceutical formulation to a patient, and spray drying the aqueous dispersion after milling. 18. A process according to claim 17 in which the aqueous dispersion to be milled comprises about 10 to 30% w/w of a compound of Formula I or II, about 4 to 15% w/w of the soluble carrier, about 0.1 to 0.4% w/w of surfactant, and about 1 % w/w to 2% w/w of the anti-agglomeration agent. 19. A method of treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e. g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction and/or amyotrophic lateral sclerosis (ALS) comprising administering to the sufferer in need thereof an effective or prophylactic amount of a composition according to any one of claims 1 to 16. 20. The use of a composition according to any one of claims 1 to 16 for the manufacture of a medicament for the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e. g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction and/or amyotrophic lateral sclerosis (ALS). 21. A method of treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e. g. Giles de la Tourette's syndrome), traumatic brain injury, ti
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