Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-06
2002-10-15
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S182000
Reexamination Certificate
active
06465461
ABSTRACT:
The present invention relates to a triazine compound which is useful in the treatment of central nervous system (CNS) diseases and disorders and to its pharmaceutically acceptable derivatives, to pharmaceutical compositions containing them, to their use in the treatment of such disorders and to methods of preparation.
EP-A-0021121 and EP-A-0247892 describe 3,5-diamino triazines, for example 3,5diamino-6-(2,3dichlorophenyl)-1,2,4-triazine (lamotrigine), which are active in the treatment of disorders of the CNS and are particularly useful in the treatment of epilepsy.
The present invention relates to a 5-amino triazine derivative which is a sodium channel blocker. This compound is a surprisingly potent anti-convulsant having increased potency with respect to lamotrigine and increased selectivity in terms of CNS side-effects and inhibition of the enzyme dihydrofolate reductase. The compound is therefore useful in the treatment of CNS diseases such as epilepsy.
Accordingly, the invention provides a compound of formula (I)
i.e. 5-amino-6-[2,3,5-trichlorophenyl]-1,2,4-triazine and pharmaceutically acceptable derivatives thereof.
By pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt or solvate of the compounds of formula (1), or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof (eg. a prodrug). Reference hereinafter to the compounds of formula (I) includes the compound of formula (I) and pharmaceutically acceptable derivatives thereof.
Suitable pharmaceutically acceptable salts of the compound of formula (I) include acid addition salts formed with inorganic or organic acids, preferably inorganic acids, e.g. hydrochlorides, hydrobromides and sulphates.
Suitable prodrugs are well-known in the art and include N-acyl derivatives, for example at either of the four nitrogens in the compounds of formula (I), for example simple acyl derivatives such as acetyl, propionyl and the like or groups such as R—O—CH
2
-nitrogen or R—O—C(O)-nitrogen.
The compounds of formula (I) are particularly useful as anticonvulsants. They are therefore useful in treating epilepsy. They may be used to improve the condition of a host, typically a human being, suffering from epilepsy. They may be employed to alleviate the symptoms of epilepsy in a host “Epilepsy” is intended to include the following seizures: simple partial seizures, complex partial seizures, secondary generalised seizures, generalised seizures including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures and atonic seizures.
The compounds of formula (I) are additionally useful in the treatment of bipolar disorder, alternatively known as manic depression. Type I or II bipolar disorder may be treated. The compounds of formula (I) may thus be used to improve the condition of a human patient suffering from bipolar disorder. They may be used to alleviate the symptoms of bipolar disorder in a host. The compounds of formula (I) may also be used in the treatment of unipolar depression.
The compounds of formula (I) are useful as analgesics. They are therefore useful in treating or preventing pain. They may be used to improve the condition of a host, typically a human being, suffering from pain. They may be employed to alleviate pain in a host. Thus, the compounds of formula (I) may be used as a preemptive analgesic to treat acute pain such as musculoskeletal pain, post operative pain and surgical pain, chronic pain such as chronic inflammatory pain (eg. rheumatoid arthritis and osteoarthritis), neuropathic pain (e.g. post herpetic neuralgia, trigeminal neuralgia and sympathetically maintained pain) and pain associated with cancer and fibromyalgia. The compounds of formula (I) may also be used in the treatment or prevention of pain associated with migraine.
The compounds of formula (I) are further useful in the treatment of functional bowel disorders which include non-ulcer dyspepsia, non cardiac chest pain and in particular irritable bowel syndrome. Irritable bowel syndrome is a gastrointestinal disorder characterised by the presence of abdominal pain and altered bowel habits without any evidence of organic disease. The compounds of formula (I) may thus be used to alleviate pain associated with irritable bowel syndrome The condition of a human patient suffering from irritable bowel syndrome may thus be improved.
The compounds of formula (I) may also be useful in the treatment of neurodegenerative diseases, such as Alzheimer's disease, ALS, motor neuron disease, Parkinson's disease, muscular sclerosis, macular degeneration and glaucoma. The compounds of formula (I) may also be useful in neuroprotection and in the treatment of neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like.
The compounds of formula (I) are further useful in the treatment of tinnitus.
Still further, the compounds of formula (I) are also useful in preventing or reducing dependence on, or preventing or reducing tolerance or reverse tolerance to, a dependence inducing agent. Examples of dependence inducing agents include opioids (eg morphine), CNS depressants (eg ethanol), psychostimulants (eg cocaine) and nicotine.
There is therefore further provided by the present invention, use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in human and veterinary medicine.
There is therefore further provided by the present invention, use of a compound of formula (I) in the manufacture of a medicament for use in the treatment of a disorder substantially as hereinbefore described.
The present invention further comprises a method of treating a patient suffering from, or susceptible to, a disorder substantially as hereinbefore described, which method comprises administering to the patient a therapeutically effective amount of a compound of formula (I).
The term “treatment” as used herein includes the treatment of established disorders, and also includes the prophylaxis thereof
The precise amount of the compounds of formula (I) administered to a host, particularly a human patient, will be the responsibility of the attendant physician However, the dose employed will depend upon a number of factors including the age and sex of the patient, the precise condition being treated and its severity, and the route of administration.
The compound of formula (I) may be administered at a dose of from 0.1 to 10 mg/kg body weight per day and more particularly 0.3 to 3 mg/kg body weight per day, calculated as the free base. The dose range for adult human beings is generally from 8 to 1000 mg/day, such as from 35 to 800 mg/day, preferably 10 to 200 mg/day or 20 to 200 mg/day, calculated as the free base.
The compounds of formula (I) and their pharmaceutically acceptable derivatives are conveniently administered in the form of pharmaceutical compositions. Thus, in another aspect of the invention, we provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof adapted for use in human or veterinary medicine. Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients.
While it is possible for the compounds of formula (I) to be administered as the raw chemical, it is preferable to present it as a pharmaceutical formulation. The formulations of the present invention comprise the compounds of formula (I) thereof together with one or more acceptable carriers or diluents therefor and optionally other therapeutic ingredients. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The formulations include those suitable for oral, parenteral (including subcutaneous e.g by injection or by depot tablet, intradermal, intrathecal, intramus
Cox Brian
Healy Mark Patrick
Nobbs Malcolm Stuart
Shah Gita Punjabhai
Balasubramanian Venkataraman
Nixon & Vanderhye P.C.
Shah Mukund J.
SmithKline Beecham Corporation
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