CN1871243A - Oral neurotherapeutic cefazolin compositions - Google Patents

Abstract

The treatment of neurological disorders using cefazolin compositions and pharmaceutical compositions including oral dosage forms that include cefazolin compositions are described.

Description

Oral cefazolin composition for neurotherapy

technical field

The present invention relates to compounds and methods useful in neuropsychiatric intervention. More specifically, the present invention relates to pharmaceutical formulations and methods for the treatment of various neurological disease states using cephalosporin sulfoxides, cephalosporin sulfones, pharmaceutically acceptable salts and active esters thereof described in oral dosage forms.

Background Art and Summary of the Invention

The pharmaceutical industry has conducted extensive research aimed at discovering and commercializing drugs for the treatment of neurological disorders. The condition typically stems from an imbalance of chemicals in the brain. The overproduction or underproduction of the relevant neurochemicals and/or receptor dysfunction is believed to be associated with a number of disease states known to neurologists, psychiatrists, psychologists and other practitioners in the field of psychiatric care. Most efforts aimed at discovering new neurologically active drugs are based on the study of the interaction of agonist/antagonist drugs with one or more of the many receptors in the brain and/or their respective receptor ligands.

The present invention provides the use of oral dosage forms of cefazolin compounds and derivatives thereof as psychotherapeutic agents in the treatment of various neurological disorders.

Description of drawings

Figure 1a-b shows the effect of Δ ³ -cefazolin-1-sulfoxide (Figure 1a) and ^Δ2 -cefazolin-1-sulfoxide (Figure 1b) in a dose-response study in the seed discovery model of anxiety. result.

Figures 2a-b show the results of studies using ^Δ2 -cefazolin-1-sulfoxide in an elevated plus maze model. Figure 2a shows the waiting time to enter the closed arm, while Figure 2b shows the time in the open arm.

Figures 3a-d show the results of experiments using the sedative (serenic) activity of ^Δ2 -cefazolin-1-sulfoxide in a resident/intruder model system. Figure 3a shows the waiting time for biting, Figure 3b shows the contact time, Figure 3c shows the number of bites, and Figure 3d shows the number of flank markings.

Figures 4a-b show locomotor activity following the resident/intruder test summarized in Figures 3a-d, Figure 4a shows open field activity and Figure 4b shows sexual arousal.

Figure 5 shows the number of learning and memory errors in the radial arm maze system.

Figures 6a-c represent dopamine metabolites DOPAC (Figure 6a) and HVA (Figure 6b) and serotonin metabolites (Figure 6c) determined by electrochemical detection after treatment with ^Δ3 -cefazolin-1-sulfoxide. Levels are expressed in pg per 15 μl.

Detailed description of the invention

The present invention and the various embodiments described and claimed herein arise, in part, from the discovery that certain carboxypeptidase E inhibitors exhibit potent neurotherapeutic activity when administered to provide their effective threshold enzyme-inhibiting concentration in the brain. This inhibitor exhibited clinically significant neurological activity evidenced in part by behavioral changes and cognitive enhancement. Based on available experimental data and molecular modeling studies, it is now suggested that neurogenic carboxypeptidase E can be targeted/inhibited to provide the basis for diverse neurotherapeutic effects. Carboxypeptidase E binding site models have identified certain cephalosporin sulfoxides and sulfones, exemplified by ^Δ2- and ^Δ3 -cefazolin sulfoxide, as potential inhibitors of carboxypeptidase E. While cefazolin itself has some sedative activity, both Δ ² - and Δ ³ -cefazolin sulfoxide have been shown to have both sedative and anxiolytic activity. Furthermore, while cefazolin is known to have some antibacterial activity when administered parenterally, the cephalosporin sulfoxides and sulfones of the present invention exhibit both sedative and antimicrobial activity in hamsters even when administered orally. Has anxiolytic activity. Accordingly, one embodiment of the present invention is Δ ² - and Δ ³ -cefazolin sulfoxides and sulfones and derivatives thereof (see formula II below) as a therapeutic agent in the treatment of aggressive behavior, obsessive-compulsive disorder, anxiety, cognitive impairment, etc. Use of psychotherapeutic agents. In a specific embodiment, Δ ² - and Δ ³ -cefazolin sulfoxide and derivatives thereof are provided in an oral dosage form.

Examples of behavioral and cognitive disorders susceptible to treatment of the present invention include: aggression disorder, obsessive compulsive disorder, anxiety, depression, schizophrenia, ADHD, and disorders manifesting as memory/learning impairments. Preliminary animal data suggest that the methods and compositions of the present invention are useful as anti-aggression drugs for the control of impulsivity and violence exemplified by autism, Tourette's syndrome, mental retardation, psychosis, mania, Alzheimer's in the treatment of neurotherapeutic conditions and for the treatment of individuals with a history of personality disorders and inappropriate aggressive behavior. Its clinical applications also extend to, for example, as an anxiolytic for the treatment of children with ADHD and behavioral disorders, and as a cognitive enhancer for the elderly population to improve learning and memory and to ameliorate loss of orientation perception. According to the present invention, cephalosporin sulfoxides and sulfones, exemplified by oral dosage forms of [Delta] ^2- and [Delta ^]3 -cefazolin sulfoxide and derivatives thereof, are useful in a variety of psychotherapeutic applications.

The neurotherapy cephalosporin compound used to prepare the oral dosage form of the present invention is usually a compound of the following formula

Formula Ia Formula Ib

where n is 1 or 2;

R is hydrogen, an active ester-forming group, or a pharmaceutically acceptable cation;

^R is hydrogen; optionally substituted alkyl, including lower alkyl and C ₁ -C ₄ alkyl, such as methyl, ethyl, propyl, etc.; optionally substituted alkoxy, including lower alkyl Oxygen and the group (C ₁ -C ₄ alkyl)-O-; or optionally substituted alkylthio, such as lower alkylthio and the group (C ₁ -C ₄ alkyl)-S-, including Methylthio and ethylthio;

Acyl is the residue of a carboxylic acid such as ^R2 - _CO2H , wherein ^R2 is alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, each of which may be optionally substituted; and

X is hydrogen, alkyl (including lower alkyl and C ₁ -C ₆ alkyl), halo, haloalkyl, hydroxy, alkoxyalkyl, haloalkoxyalkyl, alkoxyalkoxy, alkylthio radical, optionally substituted arylthio, optionally substituted heteroarylthio, acyloxy (wherein acyl is as described above) such as optionally substituted alkylcarbonyloxy, optionally substituted aryl carbonyloxy and optionally substituted heteroarylcarbonyloxy; or X is _-CH2B , where B is the residue of the nucleophile BH.

Illustratively, an acyl group is a residue attached at an (*) atom having the following structure:

wherein R is at each instance independently selected from hydrogen, optionally substituted alkyl, and a pharmaceutically acceptable cation; and each aryl or heteroaryl group forming part of an acyl group described herein is optionally substituted.

Nucleophiles B-H are any nucleophiles capable of displacing a leaving group (L) on a molecule such as a compound of the formula or a protected derivative thereof:

Formula Ic

where n is 1 or 2;

R is hydrogen, an active ester-forming group, or a pharmaceutically acceptable cation;

R1 is hydrogen, alkyl, alkoxy or alkylthio;

Acyl is as defined in compounds of formulas Ia and Ib; and

L is a leaving group, such as halo, alkoxy, aryloxy, alkylcarbonyloxy, haloalkylcarbonyloxy, arylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy groups, and their substituted derivatives.

Illustratively, X is _-CH2B , where B is a residue attached at the (*) atom having one of the following structures:

wherein R is at each instance independently selected from hydrogen, optionally substituted alkyl, and a pharmaceutically acceptable cation; and each heteroaryl forming part of X described herein is optionally substituted.

Illustratively, the cephalosporin compound for neurotherapy is a cefazolin derivative, and has the structure of the following formula:

Formula II

in:

n is 1 or 2;

one of bond a and bond b is a double bond; and

R is hydrogen, an active ester forming group or a pharmaceutically acceptable cation.

More illustratively, neurotherapeutic compounds have the structure wherein Formula III is ^Δ2 -cefazolin sulfoxide (or Δ-2-cefazolin-1-sulfoxide), and Formula IV is Δ-3- Cefazolin sulfoxide (or cefazolin-1-sulfoxide).

Formula III Formula IV

Wherein n is 1 or 2, R is hydrogen or a pharmaceutically acceptable cation.

The present invention also relates to a pharmaceutical composition comprising a compound selected from above and a pharmaceutically acceptable carrier, diluent or excipient.

Common chemical terms used in the above formulas have their usual meanings. For example, the term "alkyl" includes groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3- - pentyl, neopentyl, hexyl, heptyl, octyl and the like.

The term "aryl" refers to an aromatic or heteroaromatic ring and includes groups such as furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl , tetrazolyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiadiazolyl, oxadiazolyl, naphthyl, 2,3-indanyl, fluorenyl, quinolinyl , isoquinolyl, benzodioxanyl, benzofuryl, benzothienyl, etc.

The term "optionally substituted" refers to the replacement of one or more, preferably one to three, hydrogen atoms with one or more substituents. Such substituents include groups such as C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, hydroxyl, nitro, halo, carboxyl, cyano, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkoxyalkyl, C ₁ -C ₄ haloalkoxyalkyl, amino, carboxamido, amino, mono( C ₁ -C ₄ alkyl)amino, di(C ₁ -C ₄ alkyl)amino, C ₁ -C ₄ alkylsulfonyl, C ₁ -C ₄ alkylsulfonylamino and the like.

The terms "acyl" and "alkanoyl" include groups such as formyl, acetyl, propionyl, butyryl, pentanoyl, and the like.

The term "halo" refers to fluoro, chloro, bromo and iodo.

It should be understood that terms described herein may be combined in chemically related ways. For example, the term "arylalkyl" refers to an optionally substituted aromatic or heteroaromatic ring attached to an alkyl chain, which includes, but is not limited to, benzyl, tolyl, 2-, 3-, and 4-methyl Pyridyl, pyrimidinylethyl, 2-(thien-2-yl)propyl and the like.

The term "pharmaceutically acceptable cation" refers to any cationic residue capable of combining with a neurotherapeutic compound described herein to form any pharmaceutically acceptable salt of the corresponding carboxylate salt under appropriate reaction, solvent, pH or buffer conditions. These cations can also be prepared in a conventional manner by cation exchange. It should be understood that the salt derivatives of the neurotherapeutic compounds described herein include isolated forms as well as the form existing in solution due to reaction, solvent, pH or buffer conditions.

Exemplary pharmaceutically acceptable cations include, but are not limited to, inorganic cations, including aluminum, silver; alkali metal salts such as lithium, sodium, or potassium; alkaline earth metal salts such as calcium or magnesium; and ammonium and substituted ammonium salts, among others. Exemplary pharmaceutically acceptable cations include, but are not limited to, organic cations including alkylammoniums such as triethylammonium, hydroxyalkylammoniums such as 2-hydroxyethylammonium, bis-(2-hydroxyethyl)ammonium and tris-(2 -Hydroxyethyl) ammonium, cycloalkyl ammonium such as pyrrolidinium, piperidinium, dicyclohexyl ammonium, dibenzyl ammonium, N,N-dibenzylethylene diammonium, 1-ephenammonium, N-methyl ammonium Morpholinium, ethylpiperidinium, N-benzyl-β-phenethylammonium, ammonium dehydroabietine, ammonium N,N'-didehydroabietine, ethylenediammonium, pyridiniums such as pyridine , 4-ethyl-2-picoline , quinolinium , cetylpyridinium  and tetradecylethylpyridinium ; and biguanide  and so on. Exemplary pharmaceutically acceptable cations include, but are not limited to, mixed inorganic/organic cations, including copper glycinate and the like.

The term "active ester-forming group" refers to a group forming a carboxylate derivative which is hydrolyzed in vivo to the parent carboxylic acid under appropriately selected conditions. Such groups include prodrugs. Exemplary active ester-forming groups include, but are not limited to, 1-indanyl, N-oxysuccinimide; acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, β- Acetoxyethyl, β-pivaloyloxyethyl, 1-(cyclohexylcarbonyloxy)propan-1-yl, (1-aminoethyl)carbonyloxymethyl, etc.; alkoxycarbonyl Oxyalkyl groups such as ethoxycarbonyloxymethyl, (α-ethoxycarbonyloxyethyl, etc.; dialkylaminoalkyl groups such as ethoxycarbonyloxymethyl, β-ethoxycarbonyl Oxyethyl and the like; dialkylaminoalkyl, including di(lower alkyl)aminoalkyl such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl, diethylamino Ethyl, etc.; 2-(alkoxycarbonyl)-2-enyl such as 2-(isobutoxycarbonyl)pent-2-enyl, 2-(ethoxycarbonyl)but-2-enyl, etc. etc.; and lactone groups such as 2-benzo[c]furanonyl, dimethoxy-2-benzo[c]furanonyl and the like.

Cephalosporin sulfoxides used in the preparation of exemplary oral dosage forms are typically obtained by oxidation of the corresponding 2-cephalosporin or 3-cephalosporin known in the art using peracids such as peracetic acid, m-chloroperbenzoic acid (mCPBA), etc. Compound preparation. Sulfones are also prepared analogously by oxidation of sulfoxide analogs or directly from 2-ceph, 3-ceph analogs in the presence of e.g. ruthenium tetroxide with excess oxidizing agents such as peracids, hydrogen peroxide etc. .

Based on current animal experiments, it is believed that oral dosage forms of cephalosporin sulfoxides and sulfones, exemplified by ^Δ2- and ^Δ3 -cefazolin sulfoxide and derivatives thereof, can be performed according to the present invention. Common categories of behavioral disorders treated include: aggressive disorder, obsessive-compulsive disorder, anxiety, depression, and attention deficit hyperactivity disorder (ADHD). Therefore, in one embodiment of the invention, Δ ² - or Δ ³ -cefazolin sulfoxide or a combination of Δ ² - and Δ ³ -cefazolin sulfoxide is administered as an anti-challenge drug for the control of Impulsivity and violence in patients with autism, Tourette's syndrome, mental retardation, psychosis, mania, Alzheimer's, or in patients with a history of personality disorders and inappropriate aggressive behavior.

Other neurological conditions that may be treated in accordance with the present invention include depression, including major depressive disorder (single episode, recurrent, melancholic), atypical depression, dysthymic depression, subsyndromal ) depression, anxious depression, delayed onset depression, depression co-morbid with cancer, diabetes or post-myocardial infarction, menopausal depression; manic-depressive disorders, psychotic depression, endogenous and reactive depression disorder, obsessive-compulsive disorder, or bulimia. In addition, peptidase inhibitors can be used to treat (alone or in combination with morphine, codeine, or dextropropoxyphene) patients with: obsessive-compulsive personality disorder, post-traumatic stress Agitation disorders, hypertension, atherosclerosis, anxiety, anorexia nervosa, panic, social phobia, stuttering, sleep disturbances, chronic fatigue, cognitive deficits associated with Alzheimer's disease, alcoholism, appetite disorders, Weight loss, agoraphobia, improved memory, amnesia, smoking cessation, nicotine withdrawal syndrome symptoms, mood and/or appetite disturbances associated with PMS, depressed mood and/or sugar associated with PMS Cravings, mood disorders, appetite disorders or disorders contributing to relapses associated with nicotine withdrawal, circadian rhythm disorders, borderline personality disorder, hypochondria, premenstrual syndrome (PMS), late luteal phase dysphoria, premenstrual Dysphoria, trichotillomania, symptoms after discontinuation of other antidepressants, aggressive/intermittent rage disorder, compulsive gambling, compulsive consumption, compulsive sexual behavior, psychotropic substance use disorders, sexual function Disorder, schizophrenia, premature ejaculation or psychiatric symptoms selected from stress, annoyance, anger, rejection sensitivity and lack of mental or physical energy.

Other examples of pathological, psychological conditions that may be treated in accordance with the present invention include, but are not limited to: Moderate Mental Retardation (318.00); Severe Mental Retardation (318.10); Extreme Mental Retardation (318.20); Unspecified Mental Development Delay (319.00); Autism (299.00); Pervasive Developmental Disorder NOS (299.80); Attention Deficit Hyperactivity Disorder (314.01); Conduct Disorder, group type (312.20); Conduct Disorder, solitary Aggressive (312.00); Conduct Disorder, Undifferentiated (312.90); Tourette's Disorder (307.23); Chronic Motor or Vocal Convulsions (307.22); Brief Convulsions (307.21); Convulsion NOS (307.20); Elderly Alzheimer's type primary degenerative dementia without complications (290.00); Alzheimer's type primary degenerative dementia with delirium (290.30); Senile Alzheimer's with delusions Primary degenerative dementia of the silent type (390.20); primary degenerative dementia of the senile type with depression (290.21); primary degenerative dementia of the early senile type without complications primary degenerative dementia of early senile Alzheimer's type with delirium (290.11); primary degenerative dementia of early senile Alzheimer's type with delusions (290.12); Primary degenerative dementia of early senile Alzheimer's type with depression (290.13); multi-infarct dementia, uncomplicated (290.40); multi-infarct dementia, with delirium (290.41); multi-infarct dementia , with delusional disorder (290.42); multi-infarct dementia, with depression (290.43); senile dementia NOS (290.10); presenile dementia NOS (290.10); alcohol withdrawal delirium (291.00); alcoholic hallucinations alcoholic dementia associated with alcoholism (291.20); intoxication caused by amphetamine or similar sympathomimetic drugs (305.70); delusional disorder caused by amphetamine or similar sympathomimetic drugs (292.11 ); marijuana-induced delusional disorder (292.11); cocaine-induced intoxication (305.60); cocaine-induced delirium (292.81); cocaine-induced delusional disorder (292.11); hallucinogen-induced hallucination disorder (305.30); psychedelic-induced mood disorders (292.84); psychedelic-induced post-psychedelic (Posthallucinogen) sensory disorders (292.89); intoxication by phencyclidine (PCP) or similarly acting arylcyclohexylamines (305.90); Delirium induced by cycloridine (PCP) or similarly acting arylcyclohexylamine (292.81); delirium induced by phencyclidine (PCP) or similarly acting arylcyclohexylamine (292.11); phencyclidine (PCP ) or similarly acting arylcyclohexylamines (292.84); phencyclidine (PCP) or similarly acting arylcyclohexylamines causing organic mental disorders NOS (292.90); other or unspecified neurological disorders Poisoning caused by active substances (305.90); delirium caused by other or unspecified neuroactive substances (292.81); dementia caused by other or unspecified neuroactive substances (292.82); delusional disorder caused by other or unspecified neuroactive substances (292.11) ; Other or unspecified neuroactive substances hallucinations (292.12); Other or unspecified neuroactive substances induced mood disorders (292.84); Other or unspecified neuroactive substances induced anxiety disorders (292.89); Other or unspecified neuroactive substances causing personality disorders (292.89); other or unspecified neuroactive substances causing organic mental disorders NOS (292.90); delirium (293.00); dementia (294.10); organic delusions (293.81); organic hallucinations (293.81); organic mood disorders (293.83); organic anxiety disorders (294.80); organic personality disorders (310.10); organic mental disorders (29.80); Post-traumatic stress disorder (309.89); generalized anxiety disorder (300.02); anxiety disorder NOS (300.00); "body image disorder" (300.70); hypochondriac (or hypochondriac neurosis) (300.70); (300.81); undifferentiated somatoid disorder (300.70); somatoform disorder NOS (300.70); intermittent violent disorder (312.34); kleptomania (312.32); trichophilia (312.39); and impulse control disorder NOS (312.39).

Additional examples of other pathological, psychological conditions described herein that may be treated include: Schizophrenia, catatonic, subchronic (295.21); Schizophrenia, catatonic, chronic (295.22); Schizophrenia, Catatonic, subchronic with acute onset (295.23); Schizophrenia, catatonic, chronic with acute onset (295.24); Schizophrenia, catatonic, in remission (295.55); Schizophrenia, catatonic, not Specific (295.20); Schizophrenia, disorganized, chronic (295.12); Schizophrenia, disorganized, subchronic with acute onset (295.13); Schizophrenia, disorganized, chronic with acute onset (295.14) ; Schizophrenia, disorganized, in remission (295.15); Schizophrenia, disorganized, unspecified (295.10); Schizophrenia, delusional, subchronic (295.31); Schizophrenia, delusional, chronic ( 295.32), schizophrenia, delusional, subchronic with acute onset (295.33); schizophrenia, delusional, chronic with acute onset (295.34); schizophrenia, delusional, in remission (295.35); psychotic Schizophrenia, delusional, unspecified (295.30); Schizophrenia, undifferentiated, subchronic (295.91); Schizophrenia, undifferentiated, chronic (295.92); Schizophrenia, undifferentiated, subchronic with acute onset (295.93); schizophrenia, undifferentiated, chronic with acute onset (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 onset (295.63); Schizophrenia, Residual, chronic with acute episodes (295.94); Schizophrenia, residual, in remission (295.65); Schizophrenia, residual, unspecified (295.60); Delusional (delusional) disorder (297.10); Transient Reactive psychosis (298.80); Schizophrenia-like disorder (295.40); Affective schizophrenia disorder (295.70); Induced psychosis disorder (297.30); Psychotic disorder NOS (atypical psychosis) (298.90); Disorder, mixed, severe, without psychotic features (296.63); Manic-depressive disorder, manic, mixed, severe, without psychotic features (296.43); Manic-depressive disorder, depressive, severe, without psychotic features (296.53 ); manic-depressive disorder, mixed, with psychotic features (296.64); manic-depressive disorder, manic, with psychotic features (296.44); manic-depressive disorder, depressive, with psychotic features (296.54) ; Manic-depressive disorder NOS (296.70); major depressive disorder, single episode, with psychotic features (296.24); major depressive disorder, recurrent, with psychotic features (296.34), personality disorder, delusional (301.00) ; Personality Disorder, Schizoid (301.20); Personality Disorder, Schizotypal (301.22); Personality Disorder, Socially Averse (301.70); and Personality Disorder, Borderline (301.83).

Anxiety disorders that may be treated in accordance with the present invention include: anxiety disorder (235); panic disorder (235); panic disorder with agoraphobia (300.21); panic disorder without agoraphobia (300.01); agoraphobia (300.22); social phobia (300.23); simple phobia (300.29); organic anxiety disorder (294.80); neuroactive substance anxiety disorder (292.89); separation anxiety disorder (309.21); avoidance disorder (313.21); and excessive anxiety disorder (313.00).

Effective amounts of carboxypeptidase inhibitory compounds described herein are useful in the treatment of the following pathological, psychological conditions: moderate mental retardation; severe mental retardation; extreme mental retardation; autism; attention deficit hyperactivity generalized developmental disorder NOS; conduct disorder, organizational type; conduct disorder, individual-aggressive type; Tourette's disease; senile primary degenerative dementia of the Alzheimer's type with delirium; Senile primary degenerative dementia of the Alzheimer's type; Early senile primary degenerative dementia of the Alzheimer's type; Schizophrenia, catatonic, subchronic; Schizophrenia, catatonic, chronic; Schizophrenia Schizophrenia, catatonic, subchronic with acute onset; Schizophrenia, catatonic, chronic with acute onset; Schizophrenia, catatonic, in remission; Schizophrenia, catatonic, unspecified; Schizophrenia, Disorganized, subchronic; Schizophrenia, disorganized, chronic; Schizophrenia, disorganized, subchronic with acute onset; Schizophrenia, disorganized, chronic with acute onset; Schizophrenia, disorganized, in remission Moderate; Schizophrenia, disorganized, unspecified; Schizophrenia, delusional, subchronic; Schizophrenia, delusional, chronic; Schizophrenia, delusional, subchronic with acute onset; Schizophrenia, Delusional, chronic with acute episodes; Schizophrenia, delusional, in remission; Schizophrenia, delusional, unspecified; Schizophrenia, undifferentiated, subchronic; Schizophrenia, undifferentiated, chronic ; Schizophrenia, undifferentiated, subchronic with acute onset; Schizophrenia, undifferentiated, chronic with acute onset; Schizophrenia, undifferentiated, in remission; Schizophrenia, undifferentiated, undifferentiated Specific; Schizophrenia, residual, subchronic; Schizophrenia, residual, chronic; Schizophrenia, residual, subchronic with acute onset; Schizophrenia, residual, chronic with acute onset; Psychotic Schizophrenia, residual, in remission; Schizophrenia, residual, unspecified; Delusional (delusional) disorder; Transient reactive psychosis; Schizophrenia-like disorder; Affective schizophrenia disorder; Induced psychotic disorder ;Psychotic disorder NOS (atypical psychosis); Manic-depressive disorder, mixed type, with psychotic features; Manic-depressive disorder, manic type, with psychotic features; Manic-depressive disorder, depressive type, with psychotic features; Manic-depressive disorder NOS; major depressive disorder, single episode, or recurrent, with psychotic features; personality disorder, delusional; personality disorder, schizoid; personality disorder, schizotypal; personality disorder, socially resistant; Personality disorder, borderline, anxiety disorder; panic disorder; panic disorder with agoraphobia; panic disorder without agoraphobia; agoraphobia without history of panic disorder; social phobia; simple phobia; obsessive-compulsive disorder; trauma Post-stress disorder; generalized anxiety disorder; anxiety disorder NOS; organic anxiety disorder; neuroactive substance anxiety disorder; separation anxiety disorder; avoidance disorder in childhood or adolescence; and excessive anxiety disorder.

One or more of the compounds of the present invention may be used alone or in combination with P-glycoprotein inhibitors for the treatment of the following psychiatric conditions: schizophrenia, catatonic, subchronic; schizophrenia, catatonic, chronic; psychotic Schizophrenia, catatonic, subchronic with acute onset; Schizophrenia, catatonic, chronic with acute onset; Schizophrenia, catatonic, in remission; Schizophrenia, catatonic, unspecified; Schizophrenia , disorganized, subchronic; schizophrenia, disorganized, chronic; schizophrenia, disorganized, subchronic with acute onset; schizophrenia, disorganized, chronic with acute onset; schizophrenia, disorganized, In remission; Schizophrenia, disorganized, unspecified; Schizophrenia, delusional, subchronic; Schizophrenia, delusional, chronic; Schizophrenia, delusional, subchronic with acute onset; Schizophrenia , delusional, chronic with acute episodes; schizophrenia, delusional, in remission; schizophrenia, delusional, unspecified; schizophrenia, undifferentiated, subchronic; schizophrenia, undifferentiated, Chronic; Schizophrenia, undifferentiated, subchronic with acute onset; Schizophrenia, undifferentiated, chronic with acute onset; Schizophrenia, undifferentiated, in remission; Schizophrenia, undifferentiated, Unspecified; Schizophrenia, residual, subchronic; Schizophrenia, residual, chronic; Schizophrenia, residual, subchronic with acute onset; Schizophrenia, residual, chronic with acute onset; Schizophrenia, residual, in remission; Schizophrenia, residual, unspecified; Delusional (delusional) disorder; Transient reactive psychosis; Schizophrenia-like disorder; Affective schizophrenia disorder; Induced psychosis Disorder; Psychotic disorder NOS (atypical psychosis); Manic-depressive disorder, mixed, with psychotic features; Manic-depressive disorder, manic, with psychotic features; Manic-depressive disorder, depressive, with psychotic features ; manic-depressive disorder NOS; personality disorder, delusional; personality disorder, schizotypal; personality disorder, schizotypal; personality disorder, socially resistant; and personality disorder, borderline.

Examples of psychiatric conditions most preferably treated according to the methods of the present invention include: schizophrenia, catatonic, subchronic; schizophrenia, catatonic, chronic; schizophrenia, catatonic, subchronic with acute episodes; schizophrenia Schizophrenia, catatonic, chronic with acute onset; Schizophrenia, catatonic, in remission; Schizophrenia, catatonic, unspecified; Schizophrenia, disorganized, subchronic; Schizophrenia, disorganized, chronic ; Schizophrenia, disorganized, subchronic with acute onset; Schizophrenia, disorganized, chronic with acute onset; Schizophrenia, disorganized, in remission; Schizophrenia, disorganized, unspecified; Psychotic Schizophrenia, delusional, subchronic; Schizophrenia, delusional, chronic; Schizophrenia, delusional, subchronic with acute onset; Schizophrenia, delusional, chronic with acute onset; Schizophrenia, delusional Schizophrenia, delusional, unspecified; Schizophrenia, undifferentiated, subchronic; Schizophrenia, undifferentiated, chronic; Schizophrenia, undifferentiated, subchronic with acute Episodic; Schizophrenia, undifferentiated, chronic with acute onset; Schizophrenia, undifferentiated, in remission; Schizophrenia, undifferentiated, unspecified; Schizophrenia, residual, subchronic; Psychotic Schizophrenia, residual, chronic; Schizophrenia, residual, subchronic with acute onset; Schizophrenia, residual, chronic with acute onset; Schizophrenia, residual, in remission; Schizophrenia, residual delusional (delusional) disorder; transient reactive psychosis; schizophrenia-like disorder; affective schizoid disorder; personality disorder, schizotypal; and personality disorder, schizotypal.

In a preferred aspect of the invention, treatment of anxiety is provided. Examples of anxiety disorders that may be treated using the methods of the present invention and the pharmaceutical formulations of the present invention include anxiety, panic disorder, panic disorder with agoraphobia, panic disorder without agoraphobia, agoraphobia without a history of panic disorder , social phobia, simple phobia, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, anxiety disorder NOS, organic anxiety disorder, neuroactive substance anxiety disorder, separation anxiety disorder, avoidance disorder in childhood or adolescence, and Excessive anxiety disorder.

Examples of most preferably treated anxiety disorders include panic disorder; social phobia; simple phobia; organic anxiety disorder; obsessive-compulsive disorder; post-traumatic stress disorder; generalized anxiety disorder;

It should be understood that the foregoing list is not exhaustive and that other conditions may also be treated using the compositions described herein.

When used in accordance with the present invention, effective dosages of cephalosporin sulfoxides and sulfones and their derivatives vary depending on a number of factors including, but not limited to, their inherent affinity for the target peptidase, selection route of administration, patient body weight, blood-brain barrier transport efficiency, etc. Effective dosages of the cephalosporin sulfoxides and sulfones and derivatives thereof of the present invention can be readily determined empirically using animal models in conjunction with art-recognized analytical techniques. Illustratively, oral doses may range from about 2.5 ng/kg body weight to about 30 mg/kg body weight, representing a dose of about 100 ng to about 1 g per dose. Higher or lower dosages are also appropriate when judged to be warranted by the attending physician based on the condition of the patient.

The present invention additionally provides certain pharmaceutical formulations for the treatment of behavioral or cognitive disorders. Typically, the formulation comprises one or more cephalosporin sulfoxides or sulfones of formula I, more specifically one or more ^Δ2- or ^Δ3 -cefazolin sulfoxides of formula II, and pharmaceutically acceptable carrier. The amount of the compound, when delivered by the intended route of administration, is effective to provide effective treatment and reduce the symptoms of the target behavioral or cognitive disorder or other disorder that may be treated by inhibition of carboxypeptidase E activity in the tissue in need of the compound, i.e. the brain. The amount of compound concentration that is symptomatic. The compounds used in the present invention may be combined with one or more pharmaceutically acceptable carriers and administered orally as tablets, capsules, caplets, dispersible powders, granules, lozenges, mucosal patches, sachets, etc. medication. The compound can be combined with a pharmaceutically acceptable carrier such as starch, maltose, lactose or trehalose, alone or with one or more tablet excipients and compressed into tablets or lozenges. Optionally, such tablets, caplets or capsules may be enteric coated to minimize hydrolysis/degradation in the stomach. Oral dosage forms comprise from about 0.00001 to about 99% by weight of active ingredient and from about 1 to more than 99% by weight of one or more pharmaceutically acceptable carriers and/or formulation excipients. Optionally, formulations can be formulated to provide enhanced drug half-life and brain concentration of the active ingredient by combining the compound with, for example, a P-glycoprotein inhibitor. Alternatively, the compounds can simply be co-administered with a P-glycoprotein inhibitor.

In another embodiment of the invention, the pharmaceutical formulation may comprise, for example, about 4 μg to about 100 mg of the active ingredient in combination with the vector, representing a dose of about 100 ng/kg body weight to about 30 mg/kg body weight. It is contemplated that doses of as much as about 300 mg/kg body weight may also be effective. The pharmaceutical formulation according to one embodiment of the invention is formulated for oral (po) administration, i.e., oral ingestion or buccal or sublingual administration (in the form of sachets, lozenges and/or mucosal patches ). In another embodiment, the dosage form is formulated for oral administration as an extended release dosage form to release the active ingredient over a predetermined period of time.

While the exemplary embodiments include oral dosage forms, other dosage forms are possible. For example, topical dosage forms, including transdermal patches, intranasal and suppository dosage unit formulations containing the cephalosporin sulfoxides and sulfones of the invention in combination with conventional nontoxic Pharmaceutically acceptable carriers, adjuvants and media suitable for this route of administration.

The pharmaceutical formulations of the invention may alternatively be delivered by parenteral routes of administration, including subcutaneous, intraperitoneal, intramuscular, and intravenous. Such parenteral dosage forms are typically in the form of aqueous solutions or dispersions using pharmaceutically acceptable carriers such as isotonic saline, 5% dextrose or other known pharmaceutically acceptable liquid carrier compositions.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders or lyophilizates for the extemporaneous preparation of sterile injectable solutions or dispersion. Dosage forms are, for example, sterile and stable under the conditions of manufacture and storage and are preserved against the contaminating action of microorganisms. Carriers for injectable preparations may be solvents or dispersion media containing, for example, water, ethanol or polyalcohols (such as glycerol, propylene glycol, liquid polyethylene glycol, etc.), mixtures thereof, and vegetable oils.

Parenteral dosage forms of cephalosporin sulfoxides and sulfones for the treatment of behavioral and cognitive disorders and other disease states responsive to neurogenic peptidase inhibition may also be formulated as an injectable delayed release formulation wherein the active substance is combined with Combinations of one or more natural or synthetic biodegradable or biodispersible polymers such as carbohydrates including starches, gums and etherified or esterified cellulose derivatives, polyethers, polyethers Esters (in particular polylactide, polyglycolide or polylactide-glycolide), polyvinyl alcohol, gelatin or alginate. Such dosage formulations may be prepared as microsphere suspensions, gels (of either hydrophilic or hydrophobic composition) or shaped polymer matrix implants (which are known in the art to provide delayed delivery of biologically active components). released "depot-type" drug delivery systems). Such compositions can be prepared and designed for a variety of drug release profiles using art recognized formulation techniques.

Administration of the pharmaceutical compositions used in this invention may be intermittent, or administered at a gradual, or continuous, constant, or controlled rate to a patient in need of treatment. In addition, the time of day and frequency of daily administration of the pharmaceutical formulation may vary with the condition and circumstances of the patient. The potency and optimal dosage and formulation of any given composition used within the scope of the present invention is patient dependent and can be adjusted within reason according to the judgment of the attending physician. A formulation is typically administered for a period of time sufficient to treat or prevent a disease state in a patient, eg, to alter behavioral or cognitive performance in a patient undergoing treatment. The formulations can be administered continuously using a dosing schedule of equal or reduced dosage for the prophylactic treatment of the targeted disease state.

The embodiments of the invention described above arise in part from mechanisms of action suggested by data collected from animal behavioral cognition and skill models as described below. Other embodiments of the present invention will be apparent from analysis of data obtained from the following non-limiting experimental examples of behavioral modification and cognitive performance and improvement achievable through use of the methods and formulations of the present invention An example description of .

Example

Example I

Synthesis of Δ ² - and Δ ³ -cefazolin sulfoxide sodium salt

Cefazolin - A solution of cefazolin sodium salt (998mg, 2.095mmol, purchased from ChemifarmaS.A., Madrid, Spain, Fujian Fukang Pharmaceutical Co., Ltd., Fuzhou, China) in water (100mL) was washed with 1N Aqueous HCl treatment (to pH 2.90). The resulting precipitate was filtered with suction and washed with water. The filtrate was basified (to pH 3.50) by treatment with 1 N aqueous NaOH, then extracted with ethyl acetate (2 x 20 mL). The ethyl acetate extract was dried over _Na2SO4 , filtered, evaporated, combined with _the filtered material and dried to give 751 mg (79%) of the title compound.

^Δ2- and ^Δ3 -cefazolin diphenylmethyl esters. To generate _{diphenyldiazomethane} , Pb(OAc) ₄ (986mg, 2.22mmol) was added to the stirred Benzophenone hydrazone (437mg, 2.22mmol) containing tetramethylguanidine (3.84g, 33.4mmol) in dichloromethane (40mL). After seventy minutes of reaction, the reaction was quenched by the addition of cold (-20 °C) 30% aqueous KOH (100 mL). The mixture was poured into a separatory funnel and treated with hexanes (30 mL), shaken and separated. The organic layer was washed with additional cold (-20°C) 30% KOH (100 mL), then the KOH washes were combined and back extracted with hexanes (20 mL). The hexane extracts were combined and washed with cold (-10 °C) 2% aqueous KOH (5 _x 150 mL), dried over _K2CO3 , and used in the following reaction. For esterification, a mixture of cefazolin (674 mg, 1.48 mmol) and dichloromethane (250 mL) was treated with a complete solution of diphenyldiazomethane in hexane at room temperature. After 1.5 hours, DMF (15 mL) was added and dichloromethane was slowly removed under reduced pressure at room temperature. Thirty minutes after the cefazolin had dissolved, acetic acid (2 mL) was added. DMF was removed under high vacuum, and the residue was dissolved in dichloromethane (5 mL) and added to a vigorously stirred solution of petroleum ether:hexane (1:1, 100 mL). The resulting gum was isolated, washed with petroleum ether, dissolved in dichloromethane (30 mL) and washed with saturated NaHCO ₃ (10 mL), dried over Na ₂ SO ₄ , filtered, and evaporated to give 875 mg (95%) of the title compound , respectively a mixture of 1:1.7.

Δ ² - and Δ ³ -cefazolin sulfoxide diphenylmethyl ester. A solution of Δ ² - and Δ ³ -cefazolin diphenylmethyl ester (875 mg, 1.41 mmol) in dichloromethane (20 mL) Treated with 30% _H2O2 (196 mg, 1.83 mmol) and acetic acid (339 mg, 5.64 _mmol ). The resulting biphasic mixture was stirred for 18 hours and then worked up. The mixture was partitioned between _{dichloromethane} (20 mL) and 20% aqueous _K2CO3 (30 mL). The organic extract was dried over _Na2SO4 , filtered, evaporated and the resulting oil was purified by column chromatography ( _SiO2 , Merck 70-230 mesh, 12 cm _x 5 cm) with a gradient mobile phase 50:1-40:1 - 30:1-25:1 _{CH2Cl2 :} MeOH eluted the first product, then 20:1-10:1-15:1-8:1 _{CH2Cl2 :} MeOH eluted the second product : 284 mg (32%) of the Δ ² -isomer and 511 mg (57%) of the Δ ³ -isomer, respectively. Δ ² -isomer: ¹ H-NMR (CDCl ₃ , 300MHz) δ8.92(s, 1H), 8.33(d, J=8.5Hz, 1H), 7.50-7.21(m, 10H), 6.89(s , 1H), 6.29(s, 1H), 5.57(dd, J=8.5, 4.0Hz, 1H), 5.47-5.29(m, 3H), 4.25(d, J=4.0Hz, 1H), 3.93(ABq, J=14.3Hz, 2H), 2.67(s, 3H). Δ ³ -isomer: ¹ H-NMR (CDCl ₃ , 300MHz) δ8.84 (s, 1H), 7.63 (d, J=9.6Hz, 1H), 7.40-7.25 (m, 8H), 7.13-7.02 (m, 1H), 6.93(s, 1H), 5.94(dd, J=9.6, 4.4Hz, 1H), 5.01(ABq, J=17.5Hz, 2H), 4.50(d, J=4.4Hz, 1H) , 4.33 (ABq, J=13.7Hz, 2H), 3.77 (ABq, J=18.8Hz, 2H), 2.58(s, 3H).

Δ ³ -cefazolin sulfoxide. A solution of Δ ³ -sulfoxide diphenylmethyl ester (505 mg, 793 μmol) and anisole (52 mg, 480 μmol) in dichloromethane (0.5 mL) at 0°C was washed with three Fluoroacetic acid (13 mL) was treated for 90 minutes. The solvent was removed under reduced pressure and the resulting oil was dissolved in dichloromethane (1 mL). A precipitate started to appear. Methanol was added and the resulting white precipitate was collected by suction filtration to yield 299 mg (80%) of the title compound. ¹ H-NMR (DMSO-d ₆ , 300MHz) δ13.90(bs, 1H), 9.37(s, 1H), 8.99(d, J=8.5Hz, 1H), 5.85(dd, J=8.5, 4.3Hz , 1H), 5.44(ABq, J=17.2Hz, 2H), 4.90(d, J=4.3Hz, 1H), 4.44(ABq, J=13.7Hz, 2H), 3.89(ABq, J=18.3Hz, 2H ), 2.68(s, 3H).

^Δ2 -Cefazolin sulfoxide. Starting from ^Δ2 -cefazolin sulfoxide diphenylmethyl ester (284 mg, 402 μmol), ^Δ2 -cefazolin sulfoxide was produced in a similar manner to give 190 mg (80% ) of the title compound. ¹ H-NMR (DMSO-d ₆ , 300MHz) δ13.77(bs, 1H), 9.57(d, J=7.9Hz, 1H), 9.36(s, 1H), 6.71(s, 1H), 5.51(dd , J=7.9, 3.9Hz, 1H), 5.36(ABq, J=16.8Hz, 2H), 5.18(d, J=3.9Hz, 1H), 5.08(s, 1H), 4.21(ABq, J=14.0Hz , 2H), 2.70(s, 3H).

Δ ³ -Cefazolin sulfoxide sodium salt. A solution of NaHCO ₃ (53 mg, 631 μmol) in water (6 mL) was added to a solution of cefazolin sulfoxide (297 mg, 631 μmol) in DMSO (3 mL). The resulting solution was vortexed, frozen and lyophilized to give an oil/solid mixture which was triturated with methanol/dichloromethane. The solid obtained was filtered off with suction and washed with petroleum ether, yielding 283 mg (91%) of the title compound. ¹ H-NMR (DMSO-d ₆ , 300MHz) δ9.37(s, 1H), 8.84(d, J=8.2Hz, 1H), 5.62(dd, J=8.2, 4.4Hz, 1H), 5.43(ABq , J=16.9Hz, 2H), 4.73(d, J=4.4Hz, 1H), 4.28(ABq, J=12.6Hz, 2H), 3.59(ABq, J=18.1Hz, 2H), 2.65(s, 3H ).

^Δ2 -cefazolin sulfoxide sodium salt. Starting from ^Δ2 -cefazolin sulfoxide (189 mg, 402 μmol), ^Δ2 -cefazolin sulfoxide sodium salt was prepared in a similar manner to give 160 mg (81%) of title compound. ¹ H-NMR (DMSO-d ₆ , 300MHz) δ9.56-9.46 (m, 1H), 9.36 (s, 1H), 6.31 (s, 1H), 5.50-5.10 (m, 5H), 4.35 (ABq, J=13.5Hz, 2H), 2.69(s, 3H).

Example II

Anxiety Behavior Research: Dose-Response in a Seed Discovery Model of Anxiety

Rationale: The anxious golden hamster seed discovery model is a practical and simple bioassay for screening β-lactams with CNS activity. Briefly, hamsters were fasted overnight. The following days, they were subjected to additional stress: they were removed from the cages in which they lived and placed in a new environment for a few minutes. When they were not in their home cages, sunflower seeds were hidden under a straw bedding in one corner of the cage. When the hamster was returned to the resident cage, the hamster habitually crawled along the wall for 1-2 minutes, then calmed down to find the seeds and eat them. However, animals treated with conventional anxiolytics such as chlordiazepoxide, fluoxetine or buspirone found the seeds in less than 20 seconds (King JA et al. (2001) Neuropsychobiology 45:150-155) . This shortening of the time to find seeds from minutes to seconds also occurred after treatment with certain beta-lactam antibiotics.

Experimental protocol: Male golden hamsters were housed individually in Plexiglas cages (24cm x 24cm x 20cm), maintained on a reversed light:dark cycle (14:10; lighting on at 19:00) with ad libitum access to food and water. Each of cefazolin-1-sulfoxide (Δ ³ -cefazolin sulfoxide) and Δ-2-cefazolin-1-sulfoxide (Δ ² -cefazolin sulfoxide) was administered in a series of doses in each group Tests were performed in four groups of four animals (100 ng/kg, 10 μg/kg, 1 mg/kg, and saline vehicle as control) (Fig. la-b). All experiments were performed under dim red lighting during the dark phase of the circadian cycle. All animals were fasted for 20-24 hours prior to testing. Ninety minutes after oral gavage, animals were removed from their housing cages and placed in holding cages for 2 minutes. When they were not in their home cages, six sunflower seeds were buried under a straw bedding in one corner of their home cages. Animals were randomly returned to their home cages facing any one of the empty corners, and their latency to find seeds was recorded during a five-minute observation period. Latency was analyzed using two-way ANOVA followed by a Bonferroni post hoc test.

Results: As illustrated in Figures 1a-b, both drugs at doses of 100 ng/kg to 1 mg/kg significantly (p<0.01) shortened the latency to find seeds, compared to the average latency of nearly five minutes in the saline vehicle group Compare.

SUMMARY: This data demonstrates that cefazolins administered orally to hamsters are effective in a seed-finding assay for anxiety, a highly sensitive animal model for rapid screening of anxiolytically active drugs (King JA et al. People, (2001) Neuropsychobiology 45:150-155). The model has empirical validity (McKinney, WT (1989) Basis of development of animal models in psychiatry: An overview. In: ANIMAL MODELS OF DEPRESSION, Eds. GG Koob, CLEhlers, EJ Kupfer Birkanser, Boston) i.e., anxiolytics such as hypnotic Ning, fluoxetine, and buspirone significantly shortened the time to seed discovery at doses of 1 μg/kg and higher, while drugs such as desipramine, yohimbine, and clozapine had no effect.

Example III

Anxiety Behavioral Studies: Anxiolytic Activity in the Elevated Plus-maze

An elevated plus maze was developed for assessing the effects of anxiolytic and anxiogenic drugs in rats (Pellow et al. (1985) Journal of Neuroscience Methods 14:149-167). The method is proven effective in behavioral science, physiology and pharmacology. The plus maze has two open arms and two closed arms. Rats would naturally enter the open arm less (light), more access to the closed arm (dark), and spend significantly less time in the open arm. Restriction to the open arm involved significantly more anxiety-related behaviors and higher levels of stress hormones compared to restriction to the closed arm. Clinically effective anxiolytics such as chlordiazepoxide or diazepam significantly increased the percentage of time spent in the open arm and the number of entries into the open arm. Conversely, anxiogenic compounds such as yohimbine or amphetamine decreased the number of entries into the open arm and the time spent in the open arm.

Methods: Male Wistar rats weighing 250-300 g were housed in groups on a normal 12:12 light-dark cycle with light on at 08:00 and ad libitum access to food and water. The plus maze consists of two open arms 50 x 10 cm, and two closed arms 50 x 10 x 40 cm, open at the top, arranged so that the two open arms face each other. Raise the maze to a height of 50 cm. After oral gavage of vehicle, or 100 ng/kg, 10 μg/kg, or 1 mg/kg of Δ-2-cefazolin-1-sulfoxide (Δ ² -cefazolin sulfoxide), each Group four groups of five animals for a 90-minute test. At the start of the trial, place the animal in the center of the plus maze facing the closed arm. During the 3 min observation period, the animal's waiting time to enter the closed arm, the time spent in the closed arm and the number of times the animal entered the open arm after first entering the closed arm were recorded.

Results: Treatment with Δ-2-cefazolin-1-sulfoxide (Δ ² -cefazolin sulfoxide) increased the latency to enter the closed arm compared to vehicle (p<0.05) (Fig. 2a) , while the time spent in the open arm was significantly increased compared to vehicle (p<0.01) (Fig. 2b).

Summary: Oral administration of Δ ² -cefazolin sulfoxide to rats exhibits dose-dependent anxiolytic activity in the elevated plus maze.

Example IV

sedative activity test

The winning behavior of animals can be divided into offensive attack or defensive attack (Blanchard, R.J., Blanchard, D.C. (1977) Physiology and Behavior, 1, 197-224; Adams, D.B. (1979) The Behavioral Brain Sciences, 2, 201- 241; Albert, D.J. and Walsh, M.L. (1984) Neufoscience and Behavioral Reviews, 8, 5-24). Offensive attack is characterized by the aggressor launching an attack on the opponent, whereas defensive attack has no active approach. Both aggressive behaviors have their own unique neurobehavioral systems. The stimuli eliciting offensive and defensive aggression are different, just as the sequence of behaviors that accompany each winning response is different, although much empirical data supporting the notion of distinct offensive and defensive neural networks has been collected from animal models that exhibit similar neuronal There are also interesting and convincing parallels in the constitutive human aggressive behavior (Blanchard, D.C. (1984) Applicability of animal models to human aggression In: Biological Perspectives on Aggression, Alan R. Liss, Inc. pgs 49-74). Aggressive aggression is readily studied using male golden hamsters tested in the resident/intruder paradigm (an established aggressive aggression model) (Ferris, C.F., Potegal, M. (1988) Physiology and Behavior, 44, 235- 239). Placing an unfamiliar male hamster in a cage occupied by another male hamster elicits a defined sequence of animal-competing behaviors, including aggressive aggression, initiated by the occupant.

Animal care: Male Syrian golden hamsters (Mesocricetus auratus) (140-150 g) from Harlan Sprague-Dawley Laboratories (Indianapolis, IN) were housed individually in Plexiglas cages (24 cm x 24 cm x 20 cm) maintained on a reverse light:dark cycle (14L:10D; lighting at 19:00) and unlimited food and water. Animals were acclimated to a reversed light:dark cycle for at least two weeks prior to testing. All behavioral experiments were performed during the dark period of the circadian cycle.

Behavioral Measurements and Analysis: Hamsters are nocturnal animals, therefore, behavioral testing was performed during the first four hours of the dark period under dim red lighting. Occupant aggressive aggression was recorded during the 10-minute test period, e.g., waiting time to bite the intruder, total contact time with the intruder, total number of bites, and flank markings (Ferris, C.F., Potegal, M. (1988 ) Physiology and Behavior, 44, 235-239). The flank gland is marked as a form of olfactory communication in which the hamster arches its back against an object in the environment and rubs the flank gland producing pheromones (Johnston, R.E. (1985) Communication, In: THE HAMSTER REPRODUCTION AND BEHAVIOR. Ed Siegel, H.I. Plenum Press , NewYork, pp 121-154). The frequency of flank markings increases greatly during an encounter and is particularly enhanced when dominant animals initiate and win fights (Ferris, C.F., et al., (1987) Physiology and Behavior, 40, 661-664).

Parametric data: ie, waiting time and contact time, were analyzed by one-way ANOVA followed by Newman-Keuls post hoc test. Non-parametric data: ie, number of bites and flank markings, were analyzed using the Kruskal-Wallis test followed by the Mann-Whitney U test to determine differences between groups.

Methods: Δ-2-cefazolin-1-sulfoxide (Δ ² - Cefazolin sulfoxide) (Fig. 3a-d). Ninety minutes after oral gavage, the intruders were placed in resident cages, and resident aggression was recorded. Following aggressive behavior testing, animals were screened for locomotor activity in the open field model and in sexual arousal (Fig. 4a-b).

Results: By Δ-2-cefazolin-1-sulfoxide (Δ ² -cefazolin sulfoxide) treatment, the waiting time for biting was significantly increased and the number of biting was decreased (p<0.01). Although exposure time was significantly shortened at the highest dose, flank markers were significantly increased.

Summary: These data indicate that Δ-2-cefazolin-1-sulfoxide (Δ ² -cefazolin sulfoxide) is a very effective sedative, inhibiting aggressive aggression. There was no reduction in flank-marked, olfactory-driven behavior. As shown in Figure 4a–b, there were no changes in locomotor activity or sexual arousal, suggesting that the reduction in aggressive behavior was not due to reduced activity or appetite behavior.

Example V

Learning and memory tests in the radial arm maze

The radial arm maze is one of the most commonly used methods for examining spatial learning and memory in rodents. Developed by Olton and colleagues (Olton, D.S., Samuelson, R.J. (1976) J. Experimental Psychology, 2:97-115), this maze provides experimental subjects with the choice of several alternative passages simultaneously. Animals must use visuospatial cues to remember where food is served (place learning).

Animal care: Male BALBc mice weighing 21-23 gm were individually housed on a normal 12:12 light:dark cycle (lights on at 06:00) with ad libitum access to food and water. The method described below was reported by Crusio et al. (1987) Brain Research, 425: 182-185. The radial arm maze consists of a central platform and eight arms made of transparent Plexiglas. The central part is 22cm in diameter. The closed arms are 25cm long, 6cm high and 6cm wide. Several pellets of fresh food were placed behind the perforated wall beyond the end of each arm. This arrangement serves to prevent animals from selecting the baited arm by smelling the presence or absence of food. All arms were baited by placing food pellets (approximately 10 mg) behind a low barrier. The maze was placed on the floor and several extramaze cues were provided near the maze and between the arms. Before the start of each trial, mice were placed in the center of the maze and allowed to freely choose eight arms. Between choices, mice were confined to the center of the maze for 5 s by a transparent truncated gate at the entrance to each arm. Twenty-four hours before training, mice received a 10-min habituation trial with free access to all arms. Subsequently, the mice were deprived of food but water. During training, body weight was maintained at 85% of pre-test body weight.

Methods: Cefazolin-1-sulfoxide (Δ ³ -cefazolin sulfoxide) at a range of concentrations (saline medium, 2.5ng, 250ng, 25μg/kg) was administered using four groups of six or seven animals per group. test (Figure 5). Training was performed sixty to ninety minutes after intraperitoneal injection of 0.05 ml of Δ ³ -cefazolin sulfoxide, one trial per day for five consecutive days. The test was terminated when the animal had consumed all of the food, or after 15 minutes. One entry into the arm was counted when the mouse reached the perforated wall. An error was recorded if the animal entered the arm it had been to before. Record the number of errors for training each day. Only data from the last three days of training were used for subsequent analyses. Dose-response effects were determined by two-way ANOVA with repeated measures followed by a Bonferroni post hoc test.

Results: Treatment with Δ ³ -cefazolin sulfoxide significantly reduced (*p<0.05, **p<0.01 ) the number of errors on days 3 and 4 of the test compared to the vehicle control ( FIG. 5 ). Mice treated with vehicle showed a significant reduction in errors on day 5 compared to days 3 and 4 (p<0.05). On day five, there were no significant differences between the number of errors in any of the treatment groups and the vehicle group.

Summary: In the radiation arm maze, intraperitoneal administration of ^Δ3 -cefazolin sulfoxide reduced the number of incorrect arm entries compared to vehicle controls, indicating an improvement in spatial memory in this cognitive test. The performance of vehicle-treated mice increased over time such that their performance was substantially comparable to that of cefazolin-treated animals at the end of the five-day test period.

Example VI

Microdialysis Research

Biological studies of cefazolin-1-sulfoxide (Δ ³ -cefazolin sulfoxide), such as anxiolysis, reduction of aggressive behavior and enhancement of learning, implicate a mechanism of action involving serotonergic and catecholaminergic neurotransmission. To test this hypothesis, microdialysis was used to assess extracellular neurotransmitter levels in the nucleus accumbens region following Δ ³ -cefazolin sulfoxide treatment. The nucleus accumbens, a portion of the limbic forebrain, is known to be linked to schizophrenia, reinforcement conditioning, and drug addiction, and is thought to be involved in sensitization to early-life trauma, causing the anxiety disorders PTSD or post-traumatic stress disorder (Charney and Bremner (1999) The Neurobiology of anxiety disorder. In: Neurobiology of Mental Illness (Cahrney, DS, et al eds.), Oxford University Press, NewYork, pgs 494-517).

Methods: Twenty-four male Sprague Dawley rats were anesthetized with sodium pentobarbital (50 mg/kg) and implanted with a unilateral microdialysis guide cannula aimed at the nucleus accumbens. Animals were divided into six groups of four animals each and treated with a range of cefazolin doses (saline medium, 10 ng, 100 ng, 1 μg, 10 μg, 100 μg/kg) (Fig. 6a-c). After two days of recovery from surgery, a microdialysis probe (2 mm) was lowered into the area and connected to an infusion pump via Tygon tubing. The dialysate was artificial CSF at pH 7.4 delivered at a flow rate of 1.8 μl/min. Discard the first 30 minutes of dialysate. Thereafter, samples were collected at 15-minute intervals 45 minutes before and 75 minutes after intraperitoneal administration of Δ ³ -cefazolin sulfoxide. Samples were collected into microcentrifuge tubes containing 5 μl of 0.16N perchloric acid to stabilize catecholamines. At the conclusion of the study, animals were sacrificed and brains were prepared for microdissection to confirm the location of the microdialysis probe.

The levels of dopamine metabolites DOPAC (Fig. 6a) and HVA (Fig. 6b) and serotonin metabolite HIAA (Fig. 6c) were assessed by electrochemical detection. Samples from the first 15 minutes after intraperitoneal injection were excluded from analysis due to variability caused by handling animals for drug dosing. Individual measurements of the remaining four samples collected between 15 and 75 minutes after treatment were analyzed. For each metabolite, samples from individual animals in each group (total of 16 samples) were averaged. Means were analyzed by one-way ANOVA followed by a Bonferroni post hoc test.

Results: There was a significant (*p<0.05;**p<0.01 ) dose-dependent increase in DOPAC, HVA and HIAA levels after Δ ³ -cefazolin sulfoxide treatment.

Summary: These microdialysis studies demonstrate that Δ ³ -cefazolin sulfoxide increases serotonin and dopamine neurotransmission in the nucleus accumbens. New advances in the treatment of anxiety, impulsivity and violence have focused on the activation of serotonin neurotransmission (Feighner JP. (1999) J. Clinical Psychiatry , 60:18-22; Ferris, CF et al. (1997) J. Neuroscience, 17 :4331-4340; Coccaro et al. (1998) Archives of General Psychiatry , 55 :708-714.). Given the research in this field, it is not surprising that serotonin release from ^Δ3 -cefazolin sulfoxide in animal models is accompanied by potentiated anxiolytic and sedative behaviors.

Activation of serotonin and dopamine neurotransmission in the nucleus accumbens raises the possibility of cefazolin sulfoxide for the treatment of drug addiction, obesity, and schizophrenia. A study by scientists at the National Institute of Drug Abuse and the National Institute of Diabetes and Digestive and Kidney Diseases showed that the amphetamine analog fen Combination administration of temin and fenfluramine (PHEN/FEN) increases extracellular dopamine and serotonin levels in the nucleus accumbens of rats (Baumann et al. (2000) Synapse , 36:102-113). PHEN/FEN are effective pharmacological treatments for obesity (Weintraub et al., (1984) Archive of Internal Medicine , 144: 1143-1148) and in open clinical trials reduced cocaine craving, reduced withdrawal symptoms and prolonged drug withdrawal. Addiction (Rothman et al. (1994) J. Substance Abuse Treatment , 11:273-275). Scientists at the National Institutes of Health reasoned that drugs with mechanisms similar to those by which PHEN/FEN induce increased serotonin and dopamine neurotransmission in the nucleus accumbens might be useful in the treatment of substance abuse and obesity.

A study by scientists at Eli Lilly and Company (Indianapolis, IN) used microdialysis and ex vivo tissue analysis of the prefrontal cortex and nucleus accumbens to evaluate the efficacy of metabotropic glutamate receptor agonists being developed for psychiatric treatment. Mechanism of action (Cartmell et al. (2000) Brain Research, 887:378-384; Cartmell et al. (2000) J. Neurochemistry , 75:1147-1154). Atypical antipsychotics such as risperidone increase neurotransmission of dopamine and serotonin in the prefrontal cortex and nucleus accumbens (Cartmell et al. (2000) J. Neurochemistry , 75: 1147-1154; Hertel et al. (1996) Psychopharmacology , 124 :74-86). The Lilly scientists found that activation of metabotropic glutamate receptors has a similar mechanism to the elevation of DOPAC, HIAA, and HVA in these brain regions.

Example VII

Combining each of ^Δ2 -cefazolin sulfoxide and ^Δ3 -cefazolin sulfoxide, or a combination thereof, with a pharmaceutically acceptable tableting mixture to provide a respective tableting composition, which is compressed into a tablet or Filled into gelatin capsules such that each tablet/capsule contains 100 ng, 1 μg, 10 μg, 100 μg, 1 mg, 10 mg, 50 mg, 100 mg, 200 mg, 350 mg and 500 mg of ^Δ2- or ^Δ3 -cefazolin sulfoxide, or combinations thereof .

Example VIII

The formulation of Example VII above is administered to a patient suffering from ADHD to ameliorate the symptoms of the disease.

Example IX

A patient suffering from a neurological disorder characterized by aggressive behavior is treated with the formulation of Example VII above two to three times a day to reduce the aggressive behavior of the patient.

Example X

A patient suffering from dementia is treated with the formulation of Example VII above three times a day for improved patient cognition.

Example XI

The preparation of the above-mentioned embodiment VII is administered to patients suffering from anxiety disorder, two to three times a day, to reduce the anxiety of the patients.

While the invention has been described in detail with reference to certain preferred embodiments, there are variations and modifications within the scope and spirit of the invention as described and defined in the claims.

Claims (21)

1. Pharmaceutical preparations for neurotherapy in the form of oral dosage forms, comprising: A neurotherapeutic compound selected from the group consisting of cephalosporin sulfoxides, cephalosporin sulfones, pharmaceutically acceptable salts thereof, and active esters thereof, in amounts effective for treating and reducing the symptoms of neurological disorders; and A pharmaceutically acceptable carrier for the above compounds. 2. The pharmaceutical preparation for neurotherapy according to claim 1, wherein the compound is 2-cefotasulfoxide. 3. The pharmaceutical preparation for neurotherapy according to claim 1, wherein the compound is 3-cephoxide. 4. The pharmaceutical preparation for neurotherapy according to claim 1, wherein the compound is 2-cefsulfone. 5. The pharmaceutical preparation for neurotherapy according to claim 1, wherein the compound is 3-cefsulfone. 6. The pharmaceutical preparation for neurotherapy according to claim 1, wherein the compound is selected from the group consisting of Δ ² -cefazolin sulfoxide, Δ ³ -cefazolin sulfoxide, and Δ ² -cefazolin sulfoxide and Δ ³ -cefazolin Lin sulfoxide mixture. 7. Compounds of the formula: in n is 1 or 2; one of bond a or bond b is a double bond; and R is hydrogen, an active ester forming group or a pharmaceutically acceptable cation. 8. The compound of claim 7, wherein bond a is a double bond and bond b is a single bond. 9. A formulation comprising a compound of the following formula and a pharmaceutically acceptable carrier, diluent or excipient:

in n is 1 or 2; one of bond a or bond b is a double bond; and R is hydrogen, an active ester forming group or a pharmaceutically acceptable cation. 10. The formulation of claim 9, wherein the formulation is provided in an oral dosage form. 11. The formulation of claim 10, wherein the oral dosage form is a unit dosage form selected from the group consisting of tablets, capsules, caplets, dispersible powders, granules, lozenges, mucosal patches and sachets. 12. The formulation of any one of claims 9-11, further comprising a P-glycoprotein inhibitor. 13. A pharmaceutical preparation for neurotherapy in the form of an oral dosage form, said preparation comprising: A neurotherapeutic compound in an amount effective to treat and reduce symptoms of behavioral disorders or cognitive impairments, wherein the compound is selected from the group consisting of penicillin sulfoxide, penicillin sulfone, cephalosporin sulfoxide, cephalosporin sulfone, and pharmaceutically acceptable salts thereof; and A pharmaceutically acceptable carrier for the above compounds. 14. The pharmaceutical preparation for neurotherapy according to claim 13, wherein the oral dosage form is a unit dosage form selected from the group consisting of tablets, capsules, caplets, dispersible powders, granules, lozenges, mucosal patches and sachets. 15. The pharmaceutical preparation for neurotherapy according to claim 13, wherein the compound for neurotherapy is cephalosporin sulfoxide or cephalosporin sulfone represented by the following formula: in n is 1 or 2; R is hydrogen, an active ester-forming group, or a pharmaceutically acceptable cation; ^R is hydrogen, alkyl, alkoxy or alkylthio; Acyl is ^R2 -C(O), wherein ^R2 is optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or any optionally substituted heteroarylalkyl; and X is hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxyalkyl, haloalkoxyalkyl, alkoxyalkoxy, alkylthio, optionally substituted arylthio, optionally substituted Substituted heteroarylthio, optionally substituted alkylcarbonyloxy, optionally substituted arylcarbonyloxy, optionally substituted heteroarylcarbonyloxy, or -CH ₂ B, where B is Residues of nuclear reagent BH. 16. A method for treating behavioral disorder or cognitive disorder, comprising: the step of orally administering an effective dose of the pharmaceutical preparation for neurotherapy according to any one of claims 1-6 and 9-15. 17. A method of treating a behavioral disorder or a cognitive disorder, comprising: The step of orally administering an effective dose of a pharmaceutical preparation for neurotherapy, the pharmaceutical preparation comprising: A neurotherapeutic compound in an amount effective to treat and reduce symptoms of behavioral disorders or cognitive disorders, wherein the compound is selected from the group consisting of ^Δ2 -cefazolin sulfoxide, ^Δ3 -cefazolin sulfoxide and ^Δ2 -cefazolinsulfoxide Mixtures of sulfone and Δ ³ -cefazolin sulfoxide, and pharmaceutically acceptable salts thereof, and A pharmaceutically acceptable carrier for the above compounds. 18. A method of treating a behavioral disorder or a cognitive disorder, comprising: The step of orally administering an effective dose of a pharmaceutical preparation for neurotherapy, the pharmaceutical preparation comprising: A neurotherapeutic compound in an amount effective to treat and reduce symptoms of behavioral disorders or cognitive disorders, wherein the compound is selected from the group consisting of ^Δ2 -cefazolin sulfoxide, ^Δ3 -cefazolin sulfoxide and ^Δ2 -cefazolin sulfoxide Mixtures with Δ ³ -cefazolin sulfoxide, and pharmaceutically acceptable salts thereof, and A pharmaceutically acceptable carrier for the above compounds, Wherein the effective dose is about 1.2 ng/Kg body weight to about 30 mg/Kg body weight. 19. A pharmaceutical preparation for neurotherapy in unit dosage form, said preparation comprising: A neurotherapeutic compound selected from the group consisting of ^Δ2 -cefazolin sulfoxide, ^Δ3 -cefazolin sulfoxide and ^Δ2 -cefazolin sulfoxide and ^Δ3 -cefazolin in an amount of about 4 μg to about 100 mg Mixtures of sulfoxide, and pharmaceutically acceptable salts thereof; and A pharmaceutically acceptable carrier for the above compounds. 20. A method of treating a behavioral or cognitive disorder comprising: The step of administering an effective dose of the neurotherapeutic pharmaceutical preparation of claim 19, wherein the effective dose is about 100 ng/Kg body weight to about 1 mg/Kg body weight. 21. A method of treating a behavioral disorder or a cognitive disorder, comprising: A step of administering an effective dose of the neurotherapeutic pharmaceutical formulation of claim 19, wherein the effective dose is up to about 30 mg/Kg body weight.

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