Method for treating schizophrenia

The present invention provides a method for treating a condition selected from the group consisting of schizophrenia, schizoaffective disorder, and schizophreniform disorder in a patient using a Compound (I). ##STR1##

FIELD OF THE INVENTION
 This invention provides a method for treating or alleviating the symptoms
 of pathologic psychosis, comprising administering an effective amount of a
 cyano-oxime compound.
 BACKGROUND OF THE INVENTION
 The method of this invention provides a method for treating schizophrenia
 using compounds which were previously disclosed for use in the treatment
 of Alzheimer's Disease. The method of this invention provide the clinician
 with another treatment option for the treatment of psychotic conditions.
 The compounds used in the presently claimed method appear to have an
 acceptable side effect profile while providing surprising anti-psychotic
 activity.
 SUMMARY OF THE INVENTION
 The present invention provides a method for treating a condition selected
 from the group consisting of schizophrenia, schizophreniform disorder, and
 schizoaffective disorder, comprising administering an effective amount of
 Compound I:
 ##STR2##
 wherein
 r represents an integer of 2 to 4, s represents 1 or 2 and t represents 0
 or 1;
 R.sup.2 is a group OR.sup.4, where R.sup.4 is C.sub.1-4 alkyl, C.sub.2-4
 alkenyl, C.sub.2-4 alkynyl, a group OCOR.sup.5 where R.sup.5 is hydrogen
 or R.sup.4 ; and R.sup.3 is CN; or
 a pharmaceutically acceptable salt or solvate thereof.
 The present invention provides a method for treating a condition selected
 from the group consisting of Conduct Disorder, Solitary Aggressive Type
 (312.00), Conduct Disorder, Undifferentiated Type (312.90), Tourette's
 Disorder (307.23), Chronic Motor Or Vocal Tic Disorder (307.22), Transient
 Tic Disorder (307.21), Tic Disorder NOS (307.20), Alcohol Withdrawal
 Delirium (291.00), Alcohol Hallucinosis (291.30), Alcohol Dementia
 Associated with Alcoholism (291.20), Amphetamine or Similarly Acting
 Sympathomimetic Intoxication (305.70), Amphetamine or Similarly Acting
 Sympathomimetic Delirium (292.81), Amphetamine or Similarly Acting
 Sympathomimetic Delusional Disorder (292.11), Cannabis Delusional Disorder
 (292.11), Cocaine Intoxication (305.60), Cocaine Delirium (292.81),
 Cocaine Delusional Disorder (292.11), Hallucinogen Hallucinosis (305.30),
 Hallucinogen Delusional Disorder (292.11), Hallucinogen Mood Disorder
 (292.84), Hallucinogen Posthallucinogen Perception Disorder (292.89),
 Phencyclidine (PCP) or Similarly Acting Arylcyclohexylamine Intoxication
 (305.90), Phencyclidine (PCP) or Similarly Acting Arylcyclohexylamine
 Delirium (292.81), Phencyclidine (PCP) or Similarly Acting
 Arylcyclohexylamine Delusional Disorder (292.11), Phencyclidine (PCP) or
 Similarly Acting Arylcyclohexylamine Mood Disorder (292.84), Phencyclidine
 (PCP) or Similarly Acting Arylcyclohexylamine Organic Mental Disorder NOS
 (292.90), Other or Unspecified Psychoactive Substance Intoxication
 (305.90), Other or Unspecified Psychoactive Substance Delirium (292.81),
 Other or Unspecified Psychoactive Substance Dementia (292.82), Other or
 Unspecified Psychoactive Substance Delusional Disorder (292.11), Other or
 Unspecified Psychoactive SubstanHallucinosis (292.12), Other or
 Unspecified Psychoactive Substance Mood Disorder (292.84), Other or
 Unspecified Psychoactive Substance Anxiety Disorder (292.89), Other or
 Unspecified Psychoactive Substance Personality Disorder (292.89), Other or
 Unspecified Psychoactive Substance Organic Mental Disorder NOS (292.90),
 Delirium (293.00), Dementia (294.10), Organic Delusional Disorder
 (293.81), Organic Hallucinosis (293.82), Organic Mood Disorder (293.83),
 Organic Anxiety Disorder (294.80), Organic Personality Disorder (310.10),
 Organic Mental Disorder (294.80), Obsessive Compulsive Disorder (300.30),
 Post-traumatic Stress Disorder (309.89), Generalized Anxiety Disorder
 (300.02), Anxiety Disorder NOS (300.00), Body Dysmorphic Disorder
 (300.70), Hypochondriasis (or Hypochondriacal Neurosis) (300.70),
 Somatization Disorder (300.81), Undifferentiated Somatoform Disorder
 (300.70), Somatoform Disorder NOS (300.70), Intermittent Explosive
 Disorder (312.34), Kleptomania (312.32), Pathological Gambling (312.31),
 Pyromania (312.33), Trichotillomania (312.39), and Impulse Control
 Disorder NOS (312.39); Schizophrenia, Catatonic, Subchronic, (295.21),
 Schizophrenia, Catatonic, Chronic (295.22), Schizophrenia, Catatonic,
 Subchronic with Acute Exacerbation (295.23), Schizophrenia, Catatonic,
 Chronic with Acute Exacerbation (295.24), Schizophrenia, Catatonic, in
 Remission (295.55), Schizophrenia, Catatonic, Unspecified (295.20),
 Schizophrenia, Disorganized, Subchronic (295.11), Schizophrenia,
 Disorganized, Chronic (295.12), Schizophrenia, Disorganized, Subchronic
 with Acute Exacerbation (295.13), Schizophrenia, Disorganized, Chronic
 with Acute Exacerbation (295.14), Schizophrenia, Disorganized, in
 Remission (295.15), Schizophrenia, Disorganized, Unspecified (295.10),
 Schizophrenia, Paranoid, Subchronic (295.31), Schizophrenia, Paranoid,
 Chronic (295.32), Schizophrenia, Paranoid, Subchronic with Acute
 Exacerbation (295.33), Schizophrenia, Paranoid, Chronic with Acute
 Exacerbation (295.34), Schizophrenia, Paranoid, in Remission (295.35),
 Schizophrenia, Paranoid, Unspecified (295.30), Schizophrenia,
 Undifferentiated, Subchronic (295.91), Schizophrenia, Undifferentiated,
 Chronic (295.92), Schizophrenia, Undifferentiated, Subchronic with Acute
 Exacerbation (295.93), Schizophrenia, Undifferentiated, Chronic with Acute
 Exacerbation (295.94), Schizophrenia, Undifferentiated, in Remission
 (295.95), Schizophrenia, Undifferentiated, Unspecified (295.90),
 Schizophrenia, Residual, Subchronic (295.61), Schizophrenia, Residual,
 Chronic (295.62), Schizophrenia, Residual, Subchronic with Acute
 Exacerbation (295.63), Schizophrenia, Residual, Chronic with Acute
 Exacerbation (295.94), Schizophrenia, Residual, in Remission (295.65),
 Schizophrenia, Residual, Unspecified (295.60), Delusional (Paranoid)
 Disorder (297.10), Brief Reactive Psychosis (298.80), Schizophreniform
 Disorder (295.40), Schizoaffective Disorder (295.70), Induced Psychotic
 Disorder (297.30), Psychotic Disorder NOS (Atypical Psychosis) (298.90),
 Personality Disorders, Paranoid (301.00), Personality Disorders, Schizoid
 (301.20), Personality Disorders, Schizotypal (301.22), Personality
 Disorders, Antisocial (301.70), and Personality Disorders, Borderline
 (301.83) comprising administering an effective amount of Compound I or a
 pharmaceutically acceptable salt thereof.
 DETAILED DESCRIPTION
 As noted hereinbefore, the cyano-oxime compounds referred to herein as
 Compound I, employed in the method of the present invention are known. The
 compounds, methods of preparing the compounds, as well as pharmaceutical
 formulations containing the compounds, are taught by published Paris
 Convention Treaty Application (PCT) number WO95/31456. Thus, the artisan
 can readily prepare the Compound I materials described herein using the
 teachings in the published patent applications. To further clarify,
 Compound I shall refer to a compound of the structure:
 ##STR3##
 wherein
 r represents an integer of 2 to 4, s represents 1 or 2 and t represents 0
 or 1;
 R.sup.2 is a group OR.sup.4, where R.sup.4 is C.sub.1-4 alkyl, C.sub.2-4
 alkenyl, C.sub.2-4 alkynyl, a group OCOR.sup.5 where R.sup.5 is hydrogen
 or R.sup.4 ; and R.sup.3 is CN; or
 a pharmaceutically acceptable salt or solvate thereof. A particularly
 preferred Compound I is of the formula II:
 ##STR4##
 An especially preferred compound is known as SB202026.
 The term "alkyl" refers to the number of carbon atoms indicated; however,
 when no number is specified, the term refers to C.sub.1-6 alkyl. The alkyl
 may be linear or branched unless specified.
 The term "alkynyl" has its accepted meaning; however, if the number of
 carbon atoms are unspecified, it refers to C.sub.2-10 alkynyl. The alkynyl
 group may be linear or branched unless specified.
 The term "psychotic condition" refers to a condition wherein
 hallucinations, delusions, and/or confused thought process are
 characteristic manifestations of the named condition.
 The term "pathologic" refers to a clinically significant disease state.
 The term "effective amount", as used herein, represents an amount of
 compound necessary to prevent or treat a human susceptible to or suffering
 from a psychotic condition following administration to such human. The
 active compound is effective over a wide dosage range. For example,
 dosages per day will normally fall within the range of about 0.005 to
 about 500 mg/kg of body weight. In the treatment of adult humans, the
 range of about 0.05 to about 100 mg/kg, in single or divided doses, is
 preferred. However, it will be understood that the amount of the compound
 actually administered will be determined by a physician, in the light of
 the relevant circumstances including the condition to be treated, the
 choice of compound to be administered, the age, weight, and response of
 the individual patient, the severity of the patient's symptoms, and the
 chosen route of administration, and therefore the above dosage ranges are
 not intended to limit the scope of the invention in any way.
 The compound may further be delivered by a variety of other
 pharmaceutically accepted routes including, but in no way limited to
 parenterally, subcutaneous, intranasal, intramuscular and intravenous
 routes. Such formulations may be designed to provide delayed or controlled
 release using formulation techniques which are known in the art.
 As used herein the term "treating" includes prophylaxis of a physical
 and/or mental condition or amelioration or elimination of the developed
 physical and/or mental condition once it has been established or
 alleviation of the characteristic symptoms of such condition.
 Pathologic psychological conditions which are psychoses or may be
 associated with psychotic features include, but are not limited to the
 following disorders which have been characterized in the DSM-III-R.
 Diagnostic and Statistical Manual of Mental Disorders, Revised, 3rd Ed.
 (1980). The DSM-III-R was prepared by the Task Force on Nomenclature and
 Statistics of the American Psychiatric Association, and provides clear
 descriptions of diagnostic catagories. The numbers in parenthesis refer to
 the DSM-III-R categories. The skilled artisan will recognize that there
 are alternative nomenclatures, nosologies, and classification systems for
 pathologic psychological conditions and that these systems evolve with
 medical scientific progress.
 Examples of pathologic psychologic conditions which may be treated using
 Compound I include, but are not limited to, Conduct Disorder, Solitary
 Aggressive Type (312.00), Conduct Disorder, Undifferentiated Type
 (312.90), Tourette's Disorder (307.23), Chronic Motor Or Vocal Tic
 Disorder (307.22), Transient Tic Disorder (307.21), Tic Disorder NOS
 (307.20), Alcohol Withdrawal Delirium (291.00), Alcohol Hallucinosis
 (291.30), Alcohol Dementia Associated with Alcoholism (291.20),
 Amphetamine or Similarly Acting Sympathomimetic Intoxication (305.70),
 Amphetamine or Similarly Acting Sympathomimetic Delirium (292.81),
 Amphetamine or Similarly Acting Sympathomimetic Delusional Disorder
 (292.11), Cannabis Delusional Disorder (292.11), Cocaine Intoxication
 (305.60), Cocaine Delirium (292.81), Cocaine Delusional Disorder (292.11),
 Hallucinogen Hallucinosis (305.30), Hallucinogen Delusional Disorder
 (292.11), Hallucinogen Mood Disorder (292.84), Hallucinogen
 Posthallucinogen Perception Disorder (292.89), Phencyclidine (PCP) or
 Similarly Acting Arylcyclohexylamine Intoxication (305.90), Phencyclidine
 (PCP) or Similarly Acting Arylcyclohexylamine Delirium (292.81),
 Phencyclidine (PCP) or Similarly Acting Arylcyclohexylamine Delusional
 Disorder (292.11), Phencyclidine (PCP) or Similarly Acting
 Arylcyclohexylamine Mood Disorder (292.84), Phencyclidine (PCP) or
 Similarly Acting Arylcyclohexylamine Organic Mental Disorder NOS (292.90),
 Other or Unspecified Psychoactive Substance Intoxication (305.90), Other
 or Unspecified Psychoactive Substance Delirium (292.81), Other or
 Unspecified Psychoactive Substance Dementia (292.82), Other or Unspecified
 Psychoactive Substance Delusional Disorder (292.11), Other or Unspecified
 Psychoactive SubstanHallucinosis (292.12), Other or Unspecified
 Psychoactive Substance Mood Disorder (292.84), Other or Unspecified
 Psychoactive Substance Anxiety Disorder (292.89), Other or Unspecified
 Psychoactive Substance Personality Disorder (292.89), Other or Unspecified
 Psychoactive Substance Organic Mental Disorder NOS (292.90), Delirium
 (293.00), Dementia (294.10), Organic Delusional Disorder (293.81), Organic
 Hallucinosis (293.82), Organic Mood Disorder (293.83), Organic Anxiety
 Disorder (294.80), Organic Personality Disorder (310.10), Organic Mental
 Disorder (294.80), Obsessive Compulsive Disorder (300.30), Post-traumatic
 Stress Disorder (309.89), Generalized Anxiety Disorder (300.02), Anxiety
 Disorder NOS (300.00), Body Dysmorphic Disorder (300.70), Hypochondriasis
 (or Hypochondriacal Neurosis) (300.70), Somatization Disorder (300.81),
 Undifferentiated Somatoform Disorder (300.70), Somatoform Disorder NOS
 (300.70), Intermittent Explosive Disorder (312.34), Kleptomania (312.32),
 Pathological Gambling (312.31), Pyromania (312.33), Trichotillomania
 (312.39), and Impulse Control Disorder NOS (312.39); Schizophrenia,
 Catatonic, Subchronic, (295.21), Schizophrenia, Catatonic, Chronic
 (295.22), Schizophrenia, Catatonic, Subchronic with Acute Exacerbation
 (295.23), Schizophrenia, Catatonic, Chronic with Acute Exacerbation
 (295.24), Schizophrenia, Catatonic, in Remission (295.55), Schizophrenia,
 Catatonic, Unspecified (295.20), Schizophrenia, Disorganized, Subchronic
 (295.11), Schizophrenia, Disorganized, Chronic (295.12), Schizophrenia,
 Disorganized, Subchronic with Acute Exacerbation (295.13), Schizophrenia,
 Disorganized, Chronic with Acute Exacerbation (295.14), Schizophrenia,
 Disorganized, in Remission (295.15), Schizophrenia, Disorganized,
 Unspecified (295.10), Schizophrenia, Paranoid, Subchronic (295.31),
 Schizophrenia, Paranoid, Chronic (295.32), Schizophrenia, Paranoid,
 Subchronic with Acute Exacerbation (295.33), Schizophrenia, Paranoid,
 Chronic with Acute Exacerbation (295.34), Schizophrenia, Paranoid, in
 Remission (295.35), Schizophrenia, Paranoid, Unspecified (295.30),
 Schizophrenia, Undifferentiated, Subchronic (295.91), Schizophrenia,
 Undifferentiated, Chronic (295.92), Schizophrenia, Undifferentiated,
 Subchronic with Acute Exacerbation (295.93), Schizophrenia,
 Undifferentiated, Chronic with Acute Exacerbation (295.94), Schizophrenia,
 Undifferentiated, in Remission (295.95), Schizophrenia, Undifferentiated,
 Unspecified (295.90), Schizophrenia, Residual, Subchronic (295.61),
 Schizophrenia, Residual, Chronic (295.62), Schizophrenia, Residual,
 Subchronic with Acute Exacerbation (295.63), Schizophrenia, Residual,
 Chronic with Acute Exacerbation (295.94), Schizophrenia, Residual, in
 Remission (295.65), Schizophrenia, Residual, Unspecified (295.60),
 Delusional (Paranoid) Disorder (297.10), Brief Reactive Psychosis
 (298.80), Schizophreniform Disorder (295.40), Schizoaffective Disorder
 (295.70), Induced Psychotic Disorder (297.30), Psychotic Disorder NOS
 (Atypical Psychosis) (298.90), Personality Disorders, Paranoid (301.00),
 Personality Disorders, Schizoid (301.20), Personality Disorders,
 Schizotypal (301.22), Personality Disorders, Antisocial (301.70), and
 Personality Disorders, Borderline (301.83)
 As mentioned above, Compound I has useful antipsychotic activity. This
 activity can be demonstrated in models using well-established procedures.
 For example, the compound is assessed in a number of standard behavioral
 tests predictive of antipsychotic activity. Antagonism of
 apomorphine-induced climbing behavioral and hypothermia in mice is
 predictive of antipsychotic activity (see, Moore, N.A. et al.
 Psychopharmacology 94 (2), 263-266 (1988), and 96, 539 (1988)). Further,
 the conditioned avoidance model, as described by Davidson, A. B.
 Differential Effect of Neuroleptic and other Psychotropic Agents on
 Acquisition of Avoidance in Rats, 18 Life Sci. 127901284 (1976).
 One of the major pharmacological properties of currently employed clinical
 antipsychotic drugs in animals is their ability to block conditioned
 avoidance responding (Cook and Davidson, Psychopharmacology, A Generation
 of Progress, (Raven Press, New York: 1978) pp 563-567; Davidson and
 Weidley, Life Sci. 18:1279-1284, 1976).
 There is a high correlation between their activity and potency on a
 conditioned avoidance test and their clinical efficacy and potencies as
 antipsychotic drugs (Creese et al, Dopamine receptor binding predicts
 clinical and pharmacological properties of antischizophrenic drugs Science
 192:481-483, 1976).
 In the conditioned avoidance test, animals learn to respond during a
 conditioned stimulus in order to avoid mild shock presentation. A response
 during the conditioned stimulus is termed an avoidance response, a
 response during shock is termed an escape response; a response failure is
 when the animal fails to respond either during the conditioned stimulus or
 the shock presentation and is indicative of motor impairment. Animals
 rapidly learn to avoid 99% of the time. Antipsychotic drugs decrease the
 percentage of avoidance without interfering with the ability of the animal
 to respond since the animals do emit escape responses. The percentage of
 response failures is considered a measure of motor impairment.
 Procedure
 Rats were required to press a response lever in an experimental chamber in
 order to avoid or escape foot-shock. Each experimental session consisted
 of 50 trials. During each trial, the chamber was illuminated and a tone
 presented for a maximum of 10 seconds. A response during the tone
 immediately terminated the tone and the houselight, ending the trial. ln
 the absence of a response during the tone alone, tone plus foot shock (2.0
 mA) was presented for a maximum of 10 seconds. A response during shock
 presentation immediately terminated the shock, the tone and the
 houselight, ending the trial.
 Such studies suggest that Compound I may be especially desirable for the
 treatment of schizophrenia.
 For drug screening, a dose of 3.0 mg/kg was administered s.c. 30 minutes
 before the start of the experimental session. A drug was considered active
 if it reduced the percent avoidance responding to at least 50% without
 producing greater than 50% response failures. For active drugs, a dose
 response curve was subsequently determined.

The following Examples are studies to establish the usefulness of the named
 compounds for treating such psychotic conditions.
 EXAMPLE 1
 Human Clinical Trials
 The activity of Compound I for treating or alleviating psychosis can be
 demonstrated by human clinical trials. The study was designed as a
 double-blind, parallel, placebo-controlled multicenter trial. The patients
 are randomized into four groups, placebo and 3 other dosages of test
 compound. The dosages are administered orally with food. Patients are
 observed at four visits to provide baseline measurements. Visits 5-33
 served as the treatment phase for the study.
 During the visits, patients are observed for signs of agitation, mood
 swings, tremor, delirium, social withdrawal, and concentration abilities.
 These behaviors are indicative of the effect of the test compound on
 psychotic conditions.
 Treatment groups are compared with respect to the number and percent of
 patients who ever had the symptom during the double-blind portion of the
 study (visits 5 through 33), at a severity that was worse than during the
 baseline visits (1 through 4).