2-Hydroxymethylolanzapine compositions and methods

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C540S557000

Reexamination Certificate

active

06346528

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to methods of treating psychosis, acute mania, mild anxiety states, schizophrenia, bipolar disorder, autistic disorder, excessive aggression, substance abuse, depressive signs and symptoms, tic disorder, functional bowel disorder and fungal dermatitis.
BACKGROUND OF THE INVENTION
Olanzapine I is an orally active, potent, antipsychotic agent.
It is commercially available as Zyprexa® from Eli Lilly Co. The antipsychotic effect of olanzapine is ascribed by the literature to blocking of the dopamine D
2
receptor and to 5-HT antagonism.
One of the main serum metabolites of olanzapine is 2-hydroxymethylolanzapine II, formed by oxidation of the methyl group at the 2-position of the thiophene ring. The chemical name of II is 4-(1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepin-2-methanol and hereinafter is referred to as 2-hydroxymethylolanzapine.
Formation of 2-hydroxymethylolanzapine occurs in the liver through the enzymes of the P450 system. 2-Hydroxymethylolanzapine is formed by cytochrome P450 2D6 (CYP2D6). CYP2D6 is polymorphically expressed in the human population. The mutant allele constitutes the recessive trait. Homozygous carriers of the mutation completely lack CYP2D6 and are referred to as poor metabolizers; persons homozygous and heterozygous for the “normal” allele are extensive metabolizers. In addition to problems arising from variability in dosage regimens, the clinical use of CYP2D6-metabolized drugs and of CYP2D6 inhibitors, which includes a variety of antiarrhythmic agents, beta-adrenoceptor blockers and tricyclic antidepressants, in conjunction with olanzapine, may inhibit olanzapine metabolism.
It is therefore desirable to find a compound with the advantages of olanzapine which would provide a more predictable dosage regimen in the patient population and that would decrease the chances for drug-drug interaction.
SUMMARY OF THE INVENTION
The present invention relates to use of 2-hydroxymethylolanzapine for treating psychosis, acute mania, mild anxiety states, anxiety disorders, schizophrenia, bipolar disorder, autistic disorder, attention deficit hyperactivity disorder (“ADHD”), excessive aggression, substance abuse, depressive signs and symptoms, tic disorder, functional bowel disorder and fungal dermatitis. It provides this effective treatment while exhibiting fewer or less severe adverse effects than olanzapine, a lessened liability toward drug-drug interactions than olanzapine and a more predictable dosing regimen than olanzapine.
The invention also relates to pharmaceutical compositions comprising 2-hydroxy-methylolanzapine. In one embodiment said pharmaceutical compositions comprise solid unit dosage forms, such as tablets or capsules containing 2-hydroxymethylolanzapine.
DETAILED DESCRIPTION OF THE INVENTION
The active compound of the compositions and methods of the present invention is 2-hydroxymethylolanzapine. It may be prepared as described by Calligaro et al., [
Biorg.
&
Med. Chem. Letters,
1, 25-30, (1997)], the disclosure of which is incorporated herein by reference. Calligaro concludes that the “data demonstrate that all metabolites are significantly less active than olanzapine. It is therefore unlikely that the activity of these agents contributes to the overall pharmacological profile of the parent compound.” Galatsis [
Annual Reports in Medicinal Chemistry
32, 313, (1997)] also states that olanzapine's “ten metabolic products are inactive.” Kando et al. [
The Annals of Pharmacotherapy,
31, 1325-1334, (1997)] report that the metabolites “lack antipsychotic activity at the concentrations that have been observed.”
It has now been discovered that 2-hydroxymethylolanzapine is a superior agent for treating psychoses such as acute mania and schizophrenia, mild anxiety states, anxiety disorders, bipolar disorder, autistic disorder, attention deficit hyperactivity disorder, excessive aggression, substance abuse, depressive signs and symptoms, tic disorder, functional bowel disorder and fungal dermatitis. In particular, the methods and compositions of the present invention may be used to treat humans suffering from such conditions. 2-Hydroxymethylolanzapine provides this effective treatment while exhibiting fewer or less severe adverse effects than olanzapine, a lessened liability toward drug-drug interactions than olanzapine and a more predictable dosing regimen than olanzapine.
Adverse effects of olanzapine include postural hypotension, constipation, dry mouth, weight gain, dizziness, fast heartbeat, personality disorder and akathisia. Other side effects of olanzapine include tacycardia, irregular pulse, diaphoresis, cardiac dysrhythmia, flu syndrome, nausea, vomiting, hematuria, metrorrhagia, urinary incontinence, abdominal pain, premenstrual syndrome, somnolence, agitation, insomnia, nervousness, headache, dyspnea, tremors, myoglobinuria (rhabdomyolysis), drug-induced Parkinsonism, amblyopia and asthenia.
The present invention encompasses a method of treating psychosis which comprises administering to a human in need of such therapy, an amount of 2-hydroxy-methylolanzapine or a pharmaceutically acceptable salt thereof, said amount being sufficient to alleviate the symptoms of the psychotic condition. Psychotic conditions of particular interest in humans include, but are not limited to, ADHD, schizophrenia and acute mania.
The present invention also encompasses an oral composition which comprises a pharmaceutically acceptable carrier for oral administration and a therapeutically effective amount of 2-hydroxymethylolanzapine or a pharmaceutically acceptable salt thereof. Preferably the composition is in the form of a tablet or capsule, and the amount of 2-hydroxymethylolanzapine in the tablet or capsule is preferably about 1 to 150 mg.
A pharmaceutical composition of the present invention may also contain a therapeutically effective amount of a selective serotonin reuptake inhibitor in addition to a therapeutically effective amount of 2-hydroxymethylolanzapine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier for oral administration. Selective serotonin reuptake inhibitors include, but are not limited to paroxetine (PAXIL®), fluoxetine (PROZAC®), sertaline (ZOLOFT®), fluvoxamine (LUVOX®), venlafaxine (EFFEXOR®), and nefazodone (SERZONE®), as well as any optically pure isomers or metabolites of any of these compounds.
The present invention further encompasses a method of treating bipolar disorder, anxiety disorder, tic disorder, autistic disorder, excessive aggression, ADHD, substance abuse, and signs and symptoms of depression and of treating conditions caused by or contributed to by any of these. The method comprises administering to a human in need of such therapy, an amount of 2-hydroxy-methylolanzapine or a pharmaceutically acceptable salt thereof, said amount being sufficient to alleviate the symptoms of the particular condition.
The present invention further encompasses a method of treating fungal dermatitis and functional bowel disorder. The method comprises administering to a human in need of such therapy, an amount of 2-hydroxy-methylolanzapine or a pharmaceutically acceptable salt thereof, said amount being sufficient to alleviate the symptoms of the particular condition.
Utilizing 2-hydroxymethylolanzapine results in enhanced dosage predictability and an improved therapeutic index. In particular, 2-hydroxymethylolanzapine exhibits less variation in the patient population between so-called extensive metabolizers and poor metabolizers than does olanzapine. 2-Hydroxymethylolanzapine may also be used to treat various conditions or disorders while minimizing or avoiding adverse cardiac events associated with administration of olanzopine. Furthermore, 2-hydroxymethylolanzapine can be administered to treat various conditions or disorders while minimizing or avoiding any impact on hepatic function (e.g., liver enzyme abnormalities).
The term “psychotic condition” as used herein means pathologic psycholog

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