ZA200206651B - Compositions and methods for treatment of epilepsy. - Google Patents
Compositions and methods for treatment of epilepsy. Download PDFInfo
- Publication number
- ZA200206651B ZA200206651B ZA200206651A ZA200206651A ZA200206651B ZA 200206651 B ZA200206651 B ZA 200206651B ZA 200206651 A ZA200206651 A ZA 200206651A ZA 200206651 A ZA200206651 A ZA 200206651A ZA 200206651 B ZA200206651 B ZA 200206651B
- Authority
- ZA
- South Africa
- Prior art keywords
- pyridone
- methyl
- phenyl
- seizures
- quinolyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 12
- 239000000203 mixture Substances 0.000 title claims description 6
- 206010015037 epilepsy Diseases 0.000 title description 17
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 15
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 claims description 10
- -1 2-pyridone compound Chemical class 0.000 claims description 8
- 230000001037 epileptic effect Effects 0.000 claims description 7
- 241000124008 Mammalia Species 0.000 claims description 5
- 230000037396 body weight Effects 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- KZESGAYSFUZRJO-UHFFFAOYSA-N 1-(4-chlorophenyl)-5-methylpyridin-2-one Chemical compound C1=C(C)C=CC(=O)N1C1=CC=C(Cl)C=C1 KZESGAYSFUZRJO-UHFFFAOYSA-N 0.000 claims 1
- BUXFZDHEDVVRGV-UHFFFAOYSA-N 3-(4-chlorophenyl)-5-methyl-1-phenylpyridin-2-one Chemical compound O=C1N(C=2C=CC=CC=2)C=C(C)C=C1C1=CC=C(Cl)C=C1 BUXFZDHEDVVRGV-UHFFFAOYSA-N 0.000 claims 1
- GQDKHRWJZICYCI-UHFFFAOYSA-N 3-ethyl-1-phenylpyridin-2-one Chemical compound O=C1C(CC)=CC=CN1C1=CC=CC=C1 GQDKHRWJZICYCI-UHFFFAOYSA-N 0.000 claims 1
- ZVEJTXODUXFIAO-UHFFFAOYSA-N 5-methyl-1-(4-methylphenyl)pyridin-2-one Chemical compound C1=CC(C)=CC=C1N1C(=O)C=CC(C)=C1 ZVEJTXODUXFIAO-UHFFFAOYSA-N 0.000 claims 1
- QXUFUYWNOKGTOA-UHFFFAOYSA-N 5-methyl-1-naphthalen-1-ylpyridin-2-one Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC2=CC=CC=C12 QXUFUYWNOKGTOA-UHFFFAOYSA-N 0.000 claims 1
- 206010010904 Convulsion Diseases 0.000 description 50
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 description 22
- 229960003073 pirfenidone Drugs 0.000 description 20
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 19
- 230000000694 effects Effects 0.000 description 17
- 229960002036 phenytoin Drugs 0.000 description 16
- 239000003814 drug Substances 0.000 description 14
- 239000001961 anticonvulsive agent Substances 0.000 description 13
- 229940079593 drug Drugs 0.000 description 13
- 230000001773 anti-convulsant effect Effects 0.000 description 12
- 241000282414 Homo sapiens Species 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 7
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 7
- 210000005036 nerve Anatomy 0.000 description 6
- 241000282412 Homo Species 0.000 description 5
- 229960003965 antiepileptics Drugs 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 230000009471 action Effects 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 230000001771 impaired effect Effects 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- IRYJRGCIQBGHIV-UHFFFAOYSA-N trimethadione Chemical compound CN1C(=O)OC(C)(C)C1=O IRYJRGCIQBGHIV-UHFFFAOYSA-N 0.000 description 4
- 229960004453 trimethadione Drugs 0.000 description 4
- 206010003628 Atonic seizures Diseases 0.000 description 3
- 208000034308 Grand mal convulsion Diseases 0.000 description 3
- 206010034759 Petit mal epilepsy Diseases 0.000 description 3
- 241000283984 Rodentia Species 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 230000003556 anti-epileptic effect Effects 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 230000002920 convulsive effect Effects 0.000 description 3
- 229940064790 dilantin Drugs 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 229960002695 phenobarbital Drugs 0.000 description 3
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 3
- 101150108812 proC gene Proteins 0.000 description 3
- 210000002027 skeletal muscle Anatomy 0.000 description 3
- 230000001256 tonic effect Effects 0.000 description 3
- HQWNTNFZAGSJAX-UHFFFAOYSA-N 1-phenylpyridin-2-one Chemical class O=C1C=CC=CN1C1=CC=CC=C1 HQWNTNFZAGSJAX-UHFFFAOYSA-N 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 208000033001 Complex partial seizures Diseases 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 206010021750 Infantile Spasms Diseases 0.000 description 2
- 206010061334 Partial seizures Diseases 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 230000002151 myoclonic effect Effects 0.000 description 2
- 230000007658 neurological function Effects 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 210000003497 sciatic nerve Anatomy 0.000 description 2
- 230000001624 sedative effect Effects 0.000 description 2
- 230000001953 sensory effect Effects 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 210000000115 thoracic cavity Anatomy 0.000 description 2
- SOHMZGMHXUQHGE-UHFFFAOYSA-N 5-methyl-1h-pyridin-2-one Chemical compound CC1=CC=C(O)N=C1 SOHMZGMHXUQHGE-UHFFFAOYSA-N 0.000 description 1
- 206010051290 Central nervous system lesion Diseases 0.000 description 1
- MATGCSMQMDFTCI-UHFFFAOYSA-N ClC1=CC=C(C=C1)C=1C(N(C=C(C1)C)C1=CC=CC=C1)=O.N1C(C=CC=C1)=O Chemical compound ClC1=CC=C(C=C1)C=1C(N(C=C(C1)C)C1=CC=CC=C1)=O.N1C(C=CC=C1)=O MATGCSMQMDFTCI-UHFFFAOYSA-N 0.000 description 1
- 206010009346 Clonus Diseases 0.000 description 1
- 206010010254 Concussion Diseases 0.000 description 1
- 208000032170 Congenital Abnormalities Diseases 0.000 description 1
- 208000009078 Depressed Skull Fracture Diseases 0.000 description 1
- 208000009693 Gingival Hyperplasia Diseases 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000008457 Neurologic Manifestations Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000037158 Partial Epilepsies Diseases 0.000 description 1
- 241000270934 Rana catesbeiana Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010040703 Simple partial seizures Diseases 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 208000006633 Tonic-Clonic Epilepsy Diseases 0.000 description 1
- 206010053648 Vascular occlusion Diseases 0.000 description 1
- 201000006791 West syndrome Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 206010000269 abscess Diseases 0.000 description 1
- 208000028311 absence seizure Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000002567 autonomic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000005474 detonation Methods 0.000 description 1
- 208000013257 developmental and epileptic encephalopathy Diseases 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 238000010304 firing Methods 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000036540 impulse transmission Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000002690 local anesthesia Methods 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 230000009251 neurologic dysfunction Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 230000002232 neuromuscular Effects 0.000 description 1
- 230000008587 neuronal excitability Effects 0.000 description 1
- 230000001962 neuropharmacologic effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 230000001314 paroxysmal effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000003238 somatosensory effect Effects 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 208000021331 vascular occlusion disease Diseases 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
“ 1
Description - Compositions and Methods for Treatment of Epilepsy
A w, Technical Field ' This invention relates to certain synthesized organic compounds which demonstrate pharmacological actions characteristic of anticonvulsant (anti-epileptic) properties. The invention is based upon the discovery and demonstration that certain N-phenyl substituted 2-pyridones have marked sustained anti-convulsant properties, and suitably low levels of untoward effects.
Epilepsies are a group of disorders characterized by chronic and paroxysmal alterations in neurologic function associated with deviate changes in the electrical activity of the brain. They are estimated to occur between 0.5% and 2.0 percent of the population, and may occur at any age (“Harrison's Principles of Internal Medicine,” 13th Edition, 1994,
Isselbacher et al., Editors, McGraw-Hill, New York). Each episode of this type neurologic dysfunction is called a seizure. They may be convulsive when accompanied by motor manifestations, or may be manifest by other abnormal changes in neurologic function such as sensory, cognitive, or emotional events. Epilepsy can be induced as a result of neurologic injury or a structural brain lesion that can occur as part of other known systemic medical disorders.
About 3.0% of the United States population has recurrent, unprovoked epilepsy (W.A. Hauser, and D.C. Hesdorfer, “Epilepsy: Frequency, Causes and Consequences,” New York: Demos., 1990, 21-28). The estimated prevalence of active epilepsy is 6.4 cases per 1000 population. This means that over 1.5 million people have active epilepsy manifest as seizures (A.V. Delgado-Escueta et al., Adv. Neurol., 44:1-120, 1986).
The annual incidence of epilepsy ranges from 20 to 70 cases per 100,000 (S.D. Shorvon, Lancet £1990, 336:93-96). About 30% of patients with . seizures have an identifiable neurologic or systemic disorder (D.W.
Chadwick, Lancet, 1990, 336:291-295), and the remainder have idiopathic or " cryptogenic epilepsy. The diagnosis is based on the description of the seizures and the clinical context in which they occur. This is often further supplemented by results obtained EEG evaluations. Epileptic seizures have varied manifestations, and it becomes important to endeavor to classify the kind of seizure in order to select an appropriate and effective treatment. Since it is important to classify the type of - seizure to choose the most suitable medical treatment, a useful , classification of seizures, based on that structured by the International - League against Epilepsy in 1981 is outlined in Table 1:
Table 1. CLASSIFICATION OF EPILEPTIC SEIZURES**
Primary Generalized Seizures (convulsive or non-convulsive)
Tonic-Clonic (grand mal)
Tonic .
Absence (petit mal)
Atypical absence
Myoclonic
Atonic
Infantile spasms
Partial or Focal Seizures (beginning locally)
Simple partial seizures (without impaired consciousness)
With motor symptoms
With somatosensory or special sensory symptoms
With autonomic symptoms
With psychological symptoms .
Complex partial seizures {with impaired consciousness)
Simple partial onset followed by impaired consciousness
Impaired consciousness at onset ** “Harrison's Principles of Internal Medicine,” 13th Edition, 1994,
Isselbacher et al., Editors, McGraw-Hill, New York; M.J. Brodie and M.A.
Dichter, N.E. Jour. Med., 334:168-175, 1996.
The pathologic origins of many seizure foci in the human brain include congenital defects, head trauma and hypoxia at birth, inflammatory . vascular changes subsequent to infectious pediatric illnesses, concussions or depressed skull fracture, abscess, neoplasm, vascular occlusion. . Epilepsy is a complex disease process with various, little-understood etiologies. Despite the variety of drugs used in humans to treat epileptic seizures, 20 to 40% of epileptic patients fail to experience satisfactory seizure control with currently available drugs. A clinically useful anticonvulsant drug can affect either the initiation of an epileptic discharge, or its spread within the brain. In either case, the drug ultimately must attenuate or alter neuronal excitability. This may be ‘ attained by at least three different mechanisms: modulation of voltage- - dependent ions channels, enhancement of inhibitory pathways in the CNS, or . suppression of excitatory pathways (Rogawski et al., 1990, Pharmacol.
Rev., 42:223-286).
Two general ways are currently thought to characterize the ways by which drugs might attenuate or abolish seizures: (1) effects on pathologically altered neurons at seizure foci to prevent or reduce their initiating excessive discharge, and (2) effects that may impede or block the spread of the excitation from the initiating foci, and thereby prevent detonation and the associated disruption of normal function by aggregates of neurons located quite distant from the seizure foci. As to our knowledge of the mechanisms of action at the intracellular or molecular level, it must be admitted that mechanisms for the beneficial action of anti-epileptic agents remains poorly understood, but is currently an expanding region for many neurological investigations.
The physician who treats patients with epilepsy encounters the task of selecting an appropriate drug or combination of drugs that may best control, seizures in a given patient at an acceptable level of adverse effects. Generally, complete control (90-100%) of seizures may be attained in as much as 50% of patients, and another 25% may evidence significant reductions in the incidence of seizures.
The classification of seizures given in the above table may be further simplified in terms of clinical experience. Absence seizures respond well to one group of drugs, and generalized tonic-clonic convulsions are generally well controlled by another. Complex partial seizures tend to be refractory to any therapy, but may show some response to the second group.
Infantile spasm and akinetic, atonic and myoclonic seizures are groups ‘which respond very inadequately to the above two classes of drugs.
Furthermore, more than one anticonvulsant drug may be required to treat patients diagnosed with two or more types of seizures (L.Goodman and A. - Gilman, “The Pharmacoloical Basis of Therapeutics,” 7th Ed., 1985,
MacMillan, New York: 8th Ed., 1990, MacMillan-Pergamon, New York). . Experimentally Induced Seizures. The electroshock technique for producing experimental convulsions in the intact animal for testing chemical substances for anticonvulsant activity (T.J. Putnam and H.H.
Merritt, 1937, Science, 85:525-526) provided a practical means for the evaluation of chemical agents for the management of epilepsy prior to their administration to man. Their demonstration of anticonvulsant action and anti-epileptic efficacy of phenytoin was provided a successful " treatment for many patients with uncontrolled epilepsy. The success of their animal testing program showed that an experimental method could lead ) to the discovery of compounds that would be clinically effective. R.K.
Richards and G.M. Everett, 1944 (Fed. Proc., 3:39) found that trimethadione prevented threshold seizures induced in rodents with pentylenetetrazol, and that such seizures were also prevented by phenobarbital, but not by phenytoin. Subsequently, Goodman and associates (Proc. Am. Fed. Clin. Res., 2:100-101,1945; Jour. Phamacol. Exper. Ther., 108: 168-176, 1953) found that that phenytoin and phenobarbital, but not trimethadione, modified that pattern of experimental maximal electroshock seizures. These cited researches demonstrated in animals the significant different clinical anticonvulsant actions of these drugs. W.G.Lennox (Jour. Am. Med. Assn., 129:1069-1074, 1945; Jour. Am. Med. Assn., 134:138- 143, 1947) found that trimethadione was effective in epileptic patients suffering from petit mal, as well as myoclonic or akinetic seizures that could not be controlled by phenytoin or phenobarbital. He also found that trimethadione decreased or stopped their petit mal attacks, but failed to control grand mal attacks in 10 patients in which this type of seizure predominated (R.L. Krall et al., Epilepsia, 19:193-408, 1978).
The present invention achieves the above objects, among others, by providing, in a preferred embodiment, a method of treating a mammal with an epileptic condition, comprising: administering to said mammal a pharmaceutical composition containing an effective amount of an N-phenyl substituted 2-pyridone compound and/or pharmaceutically acceptable salts thereof.
Best Mode for Carrying Out the Invention
The present invention relates to the novel use of N-phenyl substituted \ 2-pyridone compounds having the general formula:
Ry ' On wll Jeo
N
.
A where: Rl is selected from the group consisting of (1) an alkyl group, with R3 hydrogen, and (2) hydrogen, with R3 consisting of an alkyl group; . A is an aryl group/ and R2 and R4 are hydrogen. * These compounds, including pirfenidone, S5-methyl-l-phenyl-2(1H)~- . pyridone, possess remarkable anti-convulsant properties in widely accepted experimental models of epileptic seizures. The preclinical pharmacologic and neuropharmacologic experimental tests suggest (1) oral and parenteral efficacy quite suitable for treating, various types of human epilepsy seizures and (2) a low level of side effects reflecting an absence of serious adverse reactions (absence of gum hyperplasia, absence OF depressed bone marrow function, absence of liver or kidney damage). The « safety profile for humans suggested in laboratory animal toxicity experiments appears is consistent with the low incidence of any serious adverse reactions seen thus far in more than 300 human patients with other, non-epileptic disorders (J.E. Walker ACTRIMS, (Montreal, Canada),
October 18, 1998; G. Rahgu et al., Amer. Respir. Crit. Care Med., 159:1061-1069, 1999; M, Taniyama et al., Eur. Jour. Clin. Pharmacol., 52:77-78, 1997), and unpublished inventor’s human patient files.
In laboratory animals or in man, pirfenidone is well absorbed after oral administration. Plasma pirfenidone concentrations in man peak 1 to 4 hours after dosing. Metabolically, first order kinetics prevail over a daily dose range of 1200 to 3600 milligrams of pirfenidone in divided dosage (t.i.d.). Pirfenidone is cleared primarily by hepatic metabolism (S.Giri et al., Amer. Thoracic Soc. International Conf., April 24-29, 1998) mainly hydroxylation and conjugation, and excreted primarily in the urine. None of its metabolites appears to be active against rodent experimental seizures.
The mechanism of action of pirfenidone in experimental seizures as gauged from neuropharmaclogical tests in cat and frog demonstrations, and (see below) is very similar to that of phenytoin to the extent that pirfenidone, like phenytoin, can completely block the classical after- discharge when a nerve is electronically stimulated. However, the molecular mechanism of the anticonvulsant action within neurcnal cells remains unknown.
Pirfenidone has a low level of sedative properties as compared to the . effective dose levels in laboratory experiments, and its low level of sedative activity has been observed in various human clinical trials.
The compounds can be given orally in various dosages forms, such as tablets, capsules, or solutions, or by parenteral injection in the form of
N suitable sterile solutions.
For humans, the effective anticonvulsant oral daily dosages of the - present compounds range between 5.0 and 40.0 mg/kg body weight in divided i dosages (g.i.d. or t.i.d.), and the parenteral dosages range between 2.0 and 20.0 mg/kg body weight (g.i.d. or t.i.d.). Special oral pharmceutically based long-acting formulations can be prepared to reduce dosing to only once or twice daily.
Representative 2-pyridones and reference compounds compared are: 5-methyl- l-phenyl-2(1H)-pyridone (pirfenidone) 3-methyl-1l-phenyl-2 (1H) -pyridone
S5-ethyl-1l-phenyl-2 (1H) -pyridone 1-phenyl-2 (1H) -pyridone phenytoin (Dilantin)
Effect Against Maximal Electroshock Seizures. In laboratory experimental studies by this technique, two effective compounds (5-methyl or 5-ethyl substituted, l-phenyl 2-pyridones) possess anti-convulsant properties that apprcach that known for phenytoin, a standard anti- convulsant drug for grand mal seizures. Given intraperitoneally to albino mice these compounds have afforded complete protection from maximal electroshock seizures for several hours.
To test the maximal seizure anticonvulsant properties in albino mice weighing approximately 25 grams, first an electrical current was delivered via cranial electrodes at a voltage strength which induced a typical maximal electroconvulsant seizure in all the mice. Maximal tonic electrochock seizures were induced with 2 to 7 milliamperes being discharged at 18 volts, and at a frequency of 1000 per second. Abolition of the hindlimb tonic extension component of the seizure was defined as protection in this maximal electroshock test (L.S. Goodman et al., Jour.
Pharm. Exper. Therap., 108:168, 1953). The apparatus used was structured so that the current administered was independent of external resistance.
There were 10 animals per group, and they were exposed to electroshock seizures at 20, 80 and 140 minutes after injection of the test compounds.
The mice received graded doses of the compounds, and the dose protecting 50% of the animals was calculated biometrically. Table 2 displays the calculated respective intraperitoneal doses protecting 50 percent of the mice against maximal electroshock seizures. . These results demonstrate that two (5-methyl and 5-ethyl) substituted
N-phenyl-2-pyridones are superior to the other 2-pyridones tested. The - protection lasted for about 3 hours, despite the fact that the two most effective compounds are known to be very rapidly metabolized in mice or rats (as compared to dogs or humans).
Oral or parenteral pirfenidone is readily and uniformly absorbed from the gastrointestinal tract or injection site, respectively, of laboratory animals. Oral pirfenidone is readily and uniformly absorbed from the gastrointestinal tract. Although the studied 2-pyridones are rapidly metabolized in small rodents, in rabbits, dogs, and in human subjects pirfenidone is clearly slowly metabolized as demonstrated after single dose and repeat dosage studies (S.B. Margolin and S. Lefkowitz, FASEB
Jour., B8:A382, 1994; M, Taniyama et al., Eur. Jour. Clin. Pharmacol., 52:77-78, 1997; S. Giri et al., Amex. Thoracic Soc. Intern. Conf., April 24-29, 1998).
TABLE 2
I.P. EDSQ** I.P. LD50
MG/KG MG/KG 5-methyl-1-phenyl-2-(1H)-pyridone 85 +/-~ 11 600 +/- 43 (pirfenidone) 3-methyl-1-phenyl-2~(1H)-pyridone No Activity >500 5-ethyl-1l-phenyl-2-(1H)-pyridone 60 +/~ 10 500 +/- 61 1-phenyl-2- (1H) -pyridone No Activity >500 phenytoin (Dilantin) 50 +/- 15 200 +/- 45 ** 140 minutes after injection of test compound.
The highly rapid and efficient oral bioavailability of pirfenidone in humans contrasts with that of oral phenytoin. In man, absorption of . phenytoin after oral ingestion is slow, often variable and can be ? incomplete so that peak or effective concentrations in plasma and tissues . may be delayed for 3 or more hours (E. Perucca and A.Richens, “Handbook of v Exper. Pharmacol.,” Vol. 74:831-855, 1985, Springer-Verlag, Berlin.)
Effect Against Pentylenetetrazol (Metrazol) Seizures. Table 2 displays the calculated respective oral doses protecting 50% of the mice against pentylenetetrazol-induced seizures. The pentylenetetrazol (metrazel), 120 mg/kg, was injected intraperitoneally 30 minutes after the oral administration of the respective graded doses of the compounds.
Protection in this test was defined as a failure to detect even a single episode of clonic spasms of at least 5 seconds duration during a 30 minute period following the injection of the metrazol (F.M. Berger, 78:2717, 1951). Phenytoin is known to be inactive Proc. Soc. Exper. Med. Biol., against pentylenetetrazol seizures (R.L. Krall et al., Epilepsia, 19:193- 408, 1978).
Among the cited 2-pyridones, the 5-methyl or 5-ethyl substituted compounds possess distinct neuropharmacologic effects characteristic of a standard anticonvulsant such as phenytoin.
TABLE 3
ORAL EDS50 ORAL LD50
MG/KG MG/KG 5-methyl-1l-phenyl-2-(1H)-pyridone 325 +/- 41 610 +/- 34 (pirfenidone) 3-methyl-1-~phenyl-2- (1H) -pyridone No Activity 650 +/- 110 5-ethyl-1-phenyl-2- (1H) ~-pyridone 285 +/- 29 425 +/- 48 l1-phenyl-2~ (1H) -pyridone No Activity 540 +/- 124 phenytoin (Dilantin) No Activity 490 +/- 35 mmm]
Pirfenidone: Effect on Frog Sciatic Nerve Trunk High Frequency
Stimulation. Bullfrog sciatic nerve trunk (de-sheathed) was stimulated - with trains of pulses at 200 Hertz in order to see if pirfenidone affected ) : the nerve's ability to conduct high frequency impulses. At a high - concentration of 10 mM, the drug caused definite high frequency failure, ! although it did not cause local anesthesia in the nerve. Drugs that cause "use-dependent" block (high frequency failure) are generally regarded as potential anti-epileptic drugs.
Pirfenidone: Effect on Neuromuscular Function of the Cat Soleus Muscle
Nerve Preparation. In experiments with the cat soleus muscle nerve preparation (Raines and Standaert, Epilepsia, 10:211, 1969), pirfenidone, 50 mg/kg intravenously, suppresses the post-tetanic potentiation (PTP).
The action resembles that of phenytoin (J.A. Wada, Arch. Neurol,, 34:389- 395, 1977). Neither pirfenidone nor phenytoin impair single impulse transmission. Since the PTP effect, as seen in the soleus muscle, arises from a stimulus-initiated burst of nerve firing, its suppression is equivalent to an anti-epileptic (anticonvulsant) action.
Examples of 2-pyridones found to be, or believed to be, effective in treating epilepsy are: 5-Methy-1-phenyl-2 (1H) -pyridone 5~Methyl~1-(3-nitrophenyl)-2- (1H) -pyridone 5-Methyl-1-(4’-methoxyphenyl)~2- (1H) -pyridone 5-Methyl-1-p-tolyl-2- (1H) -pyridone 5-Methyl-1-(3’-trifluoromethylphenyl)-2-(1H)-pyridone 1- (4 -Chlorophenyl) -5-methyl-2- (1H) ~pyridone 5-Methyl-1-(2’-naphthyl)-2~-(1H)-pyridone 5-Methyl-1-(1‘-naphthyl)-2- (1H) -pyridone 3-Ethyl-l-phenyl-2- (1H) -pyridone 6-Methyl-1l-phenyl-2- (1H) -pyridone 3,6-Dimethyl~l-phenyl-2~ (1H) -pyridone 5~Methyl-1-(2’-thienyl)-2- (1H) -pyridone 1-({2’-Furyl)-5-methyl-2- (1H) -pyridone 5~Methyl-1-(5’-quinolyl)~-2- (1H) -pyridone 1) 5~Methyl-1-(4’-pyridyl)-2- (1H) -pyridone 5-Methyl-1~(3’-pyridyl)-2- (1H) -pyridone , 5-Methyl-1-~(2’-pyridyl)-2-(1H)-pyridone 5-Methyl-1-(2’-quinolyl)-2- (1H) -pyridone 5-~-Methyl-1~(4’-quinolyl)-2- (1H) -pyridone 5-Methyl-1-(2’-thiazolyl)-2- (1H) -pyridone
1-(2’ -Imidazolyl)~5-methyl-2- (1H)-pyridone 5-Ethyl-1-phenyl-2- (1H) ~pyridone - 1-(4’-Nitrophenyl)-2-~ (1H) -pyridone 1,3-Diphenyl-2- (1H) —pyridone - 1-Phenyl-3-(4’-chlorophenyl)-2- (1H) -pyridone * 1,3-Diphenyl-5-methyl-2~ (1H)-pyridone 3-(4’-Chlorophenyl)-5-methyl-1-phenyl-2- (1H) -pyridone 5-Methyl-3-phenyl-1-(2’~thienyl)-2- (1H) —-pyridone :
It will thus be seen that the objects set forth above, among those elucidated in, or made apparent from, the preceding description, are efficiently attained and, since certain changes may be made in the above invention without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative only and not in a limiting sense.
It is also to be understood that the following claims are intended to cover all of the generic and specific features of the invention herein described and all statements of the scope of the invention which, as a matter of language, might be said to fall therebetween.
Claims (9)
- I claim:) 1. A method of treating a mammal with an epileptic condition, . comprising: administering to said mammal a pharmaceutical composition containing an effective amount of an N-phenyl » substituted 2-pyridone compound and/or pharmaceutically acceptable salts thereof.
- 2. A method, as defined in Claim 1, wherein: said 2-pyridone is administered in an amount of from about 2 to about 40 mg/kg of body weight per day.
- 3. A method, as defined in Claim 2, wherein: said 2-pyridone is administered orally in an amount of from about 5 to about 40 mg/kg of body weight per day.
- 4. A method, as defined in Claim 2, wherein: said 2-pyridone is administered parenterally in an amount of from about 2 to about mg/kg of body weight per day.
- 5. A method, as defined in Claim 1, wherein: said 2-pyridone has the following general structural formula: 3 Ra R | NR; Rs =0N .A
- 6. A method, as defined in Claim 1, wherein: said 2-pyridone comprises one or more compounds selected from the group consisting of: } 5-Methy-l-phenyl-2 (1H) -pyridone 5-Methyl-1- (3-nitrophenyl)-2- (1H) ~pyridone . 5-Methyl-1-(4’ -methoxyphenyl)-2- (1H) ~-pyridone 5-Methyl-1-p-tolyl-2- (1H) -pyridone 5-Methyl-1-(3’~trifluoromethylphenyl)-2~(1H)-pyridone NJ 1-(4’-Chlorophenyl)-5-methyl-2- (1H) -pyridone 5-Methyl-1-(2’-naphthyl) -2- (1H) -pyridone “ 5-Methyl-1- (1 -naphthyl)-2- (1H) -pyridone. 3-Ethyl-1-phenyl-2- (1H) -pyridone 6-Methyl-l1-phenyl-2- (1H) -pyridone - 3,6-Dimethyl-1-phenyl~2- (1H) -pyridone * 5-Methyl-1-(2’-thienyl)~-2~ (1H) -pyridone . 1-(2’-Furyl)-5-methyl-2- (1H) -pyridone hd 5-Methyl-~1-(5'-quinolyl)-2- (1H) -pyridone 5-Methyl-1-(4'-pyridyl)-2-(1H)-pyridone 5-Methyl-1~-(3’/-pyridyl)-2- (1H) -pyridone 5-Methyl-1-(2’-pyridyl)-2- (1H) -pyridone 5-Methyl-1-(2’-quinolyl)-2-(1H)-pyridone 5-Methyl-1-(4’-quinolyl)-2- (1H) -pyridone 5-Methyl-1-(2’-thiazolyl)-2- (1H) -pyridone 1-(2'-Imidazolyl)~-5-methyl-2- (1H) -pyridone . 5-Ethyl-l-phenyl-2- (1H) -pyridone 1-(4’-Nitrophenyl)-2- (1H) -pyridone 1,3-Diphenyl-2- (1H) -pyridone 1-Phenyl-3-(4’-chlorophenyl)-2- (1H) -pyridone 1,3-Diphenyl-5-methyl-2- (1H) -pyridone : 3-(4’-Chlorophenyl)-5-methyl-1-phenyl-2-(1H)-pyridone 5-Methyl-3-phenyl-1-(2/-thienyl)-2- (lH) -pyridone
- 7. A composition for treating a mammal with an epileptic condition, comprising: a pharmaceutical composition containing an effective amount of an N-phenyl substituted 2-pyridone compound and/or pharmaceutically acceptable salts thereof.
- 8. A composition, as defined in Claim 7, wherein: said pyridone has the following general structural formula: Ra; TL Rs ly NA
- 9. A composition, as defined in Claim 7, wherein: said 2- “ pyridone comprises one or more compounds selected from the group consisting of: 5-Methy-1-phenyl-2 {1H)-pyridone : 5-Methyl-1- (3-nitrophenyl)-2-(1H)-pyridone5-Methyl-1-(4’ -methoxyphenyl)-2- (1H) -pyridone 5~-Methyl-1-p-tolyl-2-(1H) -pyridone. 5-Methyl~1-(3’-trifluoromethylphenyl)-2- (1H) -pyridone ) 1-(4'-Chlorophenyl)—-5-methyl~2- (1H) -pyridone. 5-Methyl-1-(2’ -naphthyl)-2- (1H) ~pyridone = 5-Methyl-1-(1’ -naphthyl)~2- (1H) ~pyridone 3-Ethyl-1l-phenyl-2- (1H) -pyridone 6-Methyl-1-phenyl-2~ (1H) ~pyxridone 3,6-Dimethyl-1-phenyl-2- (1H) ~pyridone 5-Methyl-1-(2’-thienyl)-2-(1H)-pyridone 1-(2'-Furyl)-5-methyl-2- (1H) -pyridone 5-Methyl-1-(5’-quinolyl)~2- (1H) -pyridone 5-Methyl-1-(4'-pyridyl)-2- (1H) -pyridone 5-Methyl-1-(3’-pyridyl)-2- (1H) -pyridone 5-Methyl-1-(2’-pyridyl)-2- (1H) -pyridone 5-Methyl-1~(2’-quinolyl)~-2- (1H) ~pyridone 5-Methyl-1-(4’'-quinolyl)-2- (1H) -pyridone 5-Methyl-1-{2’-thiazolyl)-2- (1H) -pyridone 1-{2’-Imidazolyl)-5-methyl-2- (1H) -pyridone 5-Ethyl-1-phenyl-2- (1H) -pyridone 1- (4 -Nitrophenyl)-2~- (1H) -pyridone 1,3-Diphenyl-2- (1H) -pyridone 1-Phenyl-3~-(4’~-chlorophenyl)-2- (1H) -pyridone 1,3-Diphenyl-5-methyl-2- (1H) -pyridone 3-(4’-Chlorophenyl)-5-methyl-1-phenyl-2~(1H)-pyridone 5-Methyl~3-phenyl-1-(2’~thienyl)-2- (1H) ~-pyridone )
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ZA200206651A ZA200206651B (en) | 2002-08-20 | 2002-08-20 | Compositions and methods for treatment of epilepsy. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ZA200206651A ZA200206651B (en) | 2002-08-20 | 2002-08-20 | Compositions and methods for treatment of epilepsy. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200206651B true ZA200206651B (en) | 2003-10-29 |
Family
ID=30444563
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200206651A ZA200206651B (en) | 2002-08-20 | 2002-08-20 | Compositions and methods for treatment of epilepsy. |
Country Status (1)
| Country | Link |
|---|---|
| ZA (1) | ZA200206651B (en) |
-
2002
- 2002-08-20 ZA ZA200206651A patent/ZA200206651B/en unknown
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4249415B2 (en) | Pyrrolidineacetamide derivatives alone or in combination for the treatment of CNS diseases | |
| Fritsch et al. | Treatment of early and late kainic acid‐induced status epilepticus with the noncompetitive AMPA receptor antagonist GYKI 52466 | |
| US11389435B2 (en) | Compositions and methods for treating epilepsy | |
| US20060276495A1 (en) | Treatment methods of nasal congestion and nasal obstruction | |
| WO2010042780A2 (en) | Methods and compositions for treating status epilepticus and seizures causing status epilepticus | |
| MX2012001814A (en) | Use of 4-aminopyridine to improve neuro-cognitive and/or neuro-psychiatric impairment in patients with demyelinating and other nervous system conditions. | |
| CN110072521A (en) | Pharmaceutical composition comprising T-type calcium channel blocker | |
| US6956044B1 (en) | Compositions and methods for treatment of epilepsy | |
| MX2007012070A (en) | Treatment of epilepsy with non-imidazole alkylamines histamine h3-receptor ligands. | |
| EP1261338B1 (en) | Compositions and methods for treatment of epilepsy | |
| Hughes et al. | Assessment of the effect of dextromethorphan and ketamine on the acute nociceptive threshold and wind‐up of the second pain response in healthy male volunteers | |
| AU2000237125A1 (en) | Compositions and methods for treatment of epilepsy | |
| Doheny et al. | A comparison of the efficacy of carbamazepine and the novel anti‐epileptic drug levetiracetam in the tetanus toxin model of focal complex partial epilepsy | |
| JP7265526B2 (en) | epilepsy drug | |
| KR100599350B1 (en) | Combination of active principles, in particular of tetrahydropyridins and acetylcholinesterase inhibiting agents, for treating senile dementia such as alzheimer dementia | |
| Erdogan et al. | Effects of the calcium channel blocker otilonium bromide on seizure activity in rats with pentylenetetrazole-induced convulsions | |
| ZA200206651B (en) | Compositions and methods for treatment of epilepsy. | |
| Damar et al. | Alterations in the timing of huperzine A cerebral pharmacodynamics in the acute traumatic brain injury setting | |
| NL8002041A (en) | METHOD FOR PREPARING AN ANALGETIC AND MYOTONOLYTIC MEDICINAL PRODUCT | |
| JP2006519225A (en) | Pharmaceutical composition for treating addiction | |
| Liebetanz et al. | Pharmacology of transcranial direct current stimulation: missing effect of riluzole | |
| Bugay et al. | Effects of sublethal organophosphate toxicity and anti-cholinergics on electroencephalogram and respiratory mechanics in mice | |
| WO2006115302A1 (en) | Therapeutic agent for neuropathic pain | |
| LeBlanc et al. | Impact of Disease States on the Pharmacokinetics and Pharmacodynamics of Angiotensin‐Converting Enzyme Inhibitors | |
| RU2607946C2 (en) | Compositions, containing cholinesterase inhibitor for treating cognitive disorders |