Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – N-c doai
Reexamination Certificate
2002-02-21
2003-04-01
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
N-c doai
Reexamination Certificate
active
06541513
ABSTRACT:
FIELD OF THE INVENTION
This invention is directed to a method for use of a carbamate compound in preventing or treating psychotic disorders. More particularly, this invention is directed to a method for use of halogenated 2-phenyl-1,2-ethanediol monocarbamate or dicarbamate compounds for preventing or treating psychotic disorders.
BACKGROUND OF THE INVENTION
Psychotic disorders are those that are predominantly characterized by psychosis. Psychosis is an impairment of mental functioning to the extent that it interferes grossly with an individual's ability to meet the ordinary demands of life. According to the American Psychiatric Association, psychotic means grossly impaired, in terms of reality testing. Such testing would define gross impairment as existing when individuals incorrectly evaluate the accuracy of their perceptions and thoughts and make incorrect inferences about external reality, even in the face of contrary evidence. The term psychotic is also appropriate when behavior is so disorganized that it is reasonable to infer that results of reality testing would indicate an individual as grossly disturbed, for instance, by the existence of markedly incoherent speech without apparent awareness by the person that the speech is not understandable or by the agitated, inattentive and disoriented behavior observed in the phencyclidine psychotic disorder (Diagnostic and Statistical Manual of Mental Disorders, Ed. 4
th
, American Psychiatric Association, Washington, D.C. 1994; Kaplan & Sadock's Comprehensive Textbook of Psychiatry, Seventh Edition, Volume I, Lippincott Williams & Wilkins: Philadelphia, pp. 825, 2000).
Psychotic disorders include, and are not limited to, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder or psychotic disorder not otherwise specified (Diagnostic and Statistical Manual of Mental Disorders, Ed. 4
th
, American Psychiatric Association, Washington, D.C. 1994).
Schizophrenia is any of a group of psychotic disorders usually characterized by withdrawal from reality, illogical patterns of thinking, delusions and hallucinations and accompanied in varying degrees by other emotional, behavioral or intellectual disturbances (Schizophrenia, Decision Resources, Inc., December 2000). A lifelong chronic mental illness, schizophrenia exhibits several features including positive and negative symptoms, cognitive deficits, onset in young adulthood and deterioration from the previous level of functioning. Positive symptoms reflect a distortion or excess of normal functions (eg, disorganized speech, delusions, hallucinations). Negative symptoms, on the other hand, reflect a restricted range of normal behavior and emotions (eg, apathy, paucity of speech and incongruity or flattening of emotional responses). Schizophrenia can be presented in various forms depending on the symptoms and signs. The varieties of schizophrenia include paranoid schizophrenia, hebephrenic schizophrenia, catatonic schizophrenia, and undifferentiated schizophrenia as well as post-schizophrenic depression, residual schizophrenia, simple schizophrenia and unspecified schizophrenia.
Increasingly, schizophrenia is conceptualized as a complex biological disorder in which genes play a role (but not an exclusive one) and in which brain development is likely to be abnormal. Multiple abnormalities have been implicated in the pathophysiology of schizophrenia, including serotoninergic dysfunctions and abnormal dopminergic transmission which result in the impairment of sensormotor gating (Aghajanian G K, Marek G J, Serotonin model of schizophrenia: emerging role of glutamate mechanisms,
Brain Res. Rev.,
2000, 31 (2-3), 302-12; Lieberman J A, Mailman R B, Duncan G, Sikich L, Chakos M, Nichols D E, Kraus J E, Serotonergic basis of antipsychotic drug effects in schizophrenia,
Biol. Psychiatry,
1998, 44 (11), 1099-117; Veenstra-VanderWeele J, Anderson G M, Cook E H, Pharmacogenetics and the serotonin system: initial studies and future directions,
Eur. J. Pharmacol.,
2000, 410 (2-3), 165-181; Wen-Jun Gao, Leonid S. Krimer and Patricia S. Goldman-Rakic, Presynaptic regulation of recurrent excitation by D1 receptors in prefrontal circuits,
Proc. Natl. Acad. Sci. USA,
Jan. 2, 2001; 98, 1, 295-300; Anissa Abi-Dargham, Janine Rodenhiser, David Printz, Yolanda Zea-Ponce, Roberto Gil, Lawrence S. Kegeles, Richard Weiss, Thomas B. Cooper, J. John Mann, Ronald L. Van Heertum, Jack M. Gorman and Marc Laruelle, Increased baseline occupancy of D
2
receptors by dopamine in schizophrenia,
Proc. Natl. Acad. Sci. USA,
Jul. 5, 2000, 97,14, 8104-8109; and, Geyer, M. A., Krebs-Thomson, K., Braff, D. L., Swerdlow, N. R., Pharmacological studies of prepulse inhibition models of sensormotor gating deficits in schizophrenia: a decade in review,
Psychopharmacology
(Berlin, Ger.), 2001, 156, 2-3, 117-154).
Compounds that have various activities, including exhibiting 5-HT2A receptor antagonism, are effective antipsychotics (Carlsson A, Waters N, Carlsson M L, Neurotransmitter interactions in schizophrenia—therapeutic implications,
Biol. Psychiatry,
1999, 46 (10), 1388-95). For instance, antipsychotic drugs such as clozapine, olanzapine, quetiapine, risperidone, sertindole, and ziprasidone are potent 5-HT2a receptor antagonists (Meltzer H Y, The role of serotonin in antipsychotic drug action,
Neuropsychopharmacology,
1999, 21 (2 Suppl), 106S-115S; and, Lieberman J A, Mailman R B, Duncan G, Sikich L, Chakos M, Nichols D E, Kraus J E, Serotonergic basis of antipsychotic drug effects in schizophrenia,
Biol. Psychiatry,
Dec. 1, 1998, 44 (11), 1099-1117).
DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride) is an hallucinogen having high affinity and selectivity as an agonist at 5-HT2A/2C receptors (Dowd C S, Herrick-Davis K, Egan C, DuPre A, Smith C, Teitler M, Glennon R A, 1-[4-(3-Phenylalkyl)phenyl]-2-aminopropanes as 5-HT(2A) partial agonists,
J. Med. Chem.,
2000, 43 (16), 3074-84; Yan Q S, Activation of 5-HT2A/2C receptors within the nucleus accumbens increases local dopaminergic transmission,
Brain Res. Bull.,
2000, 51 (1), 75-81; Wettstein J G, Host M, Hitchcock J M, Selectivity of action of typical and atypical anti-psychotic drugs as antagonists of the behavioral effects of 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI),
Prog. Neuropsychopharmacol. Biol. Psychiatry,
1999, 23 (3), 533-44). In the DOI-induced head shake animal model, DOI administration produces dose-related behavioral effects including head shakes. In a dose-dependent manner, antipsychotics such as risperidone, haloperidol, clozapine and olanzapine antagonize the behavioral effects of DOI. Overall, the data shows that antipsychotic agents as a drug class effectively block the effects of DOI with selective activity and that non-antipsychotic drugs were generally inactive (Wettstein J G, Host M, Hitchcock J M, Selectivity of action of typical and atypical anti-psychotic drugs as antagonists of the behavioral effects of 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI),
Prog. Neuropsychopharmacol. Biol. Psychiatry,
April 1999, 23 (3), 533-44).
The prepulse inhibition (PPI) animal model (wherein a reduced startle reflex occurs in dopamine-activated rodents when a startling stimulus is preceded 30 to 500 msec by a weak stimulus or prepulse) and is predictive of clinical antipsychotic potency in a subgroup of schizophrenia patients who have dopaminergic deficits (Vollenweider, Franz X. and Geyer, Mark A., A systems model of altered consciousness: integrating natural and drug-induced psychoses,
Brain Research Bulletin,
2001, 56, 5, 495-507; Braff, D. L., Geyer, M. A. and Swerdlow, N. R., Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies,
Psychopharmacology
(Berlin, Ger.), 2001, 156, 2-3, 234-258; Geyer, M. A., Krebs-Thomson, K., Braff, D. L. and S
Plata-Salaman Carlos R.
Twyman Roy E.
Zhao Boyu
Henley III Raymond
Ortho-McNeil Pharmaceutical , Inc.
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